10-43111203-C-T

Variant names:

• chr10-43111203-C-T
• rs587780806
• NM_020975.6:c.1264-4C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS1

The NM_020975.6(RET):​c.1264-4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000614 in 1,613,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: RET NM_020975.6 splice_region, intron
• Scores: Splicing: ADA: 0.001751
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.10
• Publications: 1 publications found

Genes affected

RET (HGNC:9967): (ret proto-oncogene) This gene encodes a transmembrane receptor and member of the tyrosine protein kinase family of proteins. Binding of ligands such as GDNF (glial cell-line derived neurotrophic factor) and other related proteins to the encoded receptor stimulates receptor dimerization and activation of downstream signaling pathways that play a role in cell differentiation, growth, migration and survival. The encoded receptor is important in development of the nervous system, and the development of organs and tissues derived from the neural crest. This proto-oncogene can undergo oncogenic activation through both cytogenetic rearrangement and activating point mutations. Mutations in this gene are associated with Hirschsprung disease and central hypoventilation syndrome and have been identified in patients with renal agenesis. [provided by RefSeq, Sep 2017]

RET Gene-Disease associations (from GenCC):

• familial medullary thyroid carcinoma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• multiple endocrine neoplasia type 2A

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
• multiple endocrine neoplasia type 2B

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Hirschsprung disease, susceptibility to, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Haddad syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hirschsprung disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• renal agenesis, unilateral

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• bilateral renal agenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• renal agenesis

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 10-43111203-C-T is Benign according to our data. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43111203-C-T is described in CliVar as Benign/Likely_benign. Clinvar id is 136097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000643 (94/1461362) while in subpopulation SAS AF = 0.000487 (42/86244). AF 95% confidence interval is 0.00037. There are 0 homozygotes in GnomAdExome4. There are 55 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6	c.1264-4C>T		splice_region_variant, intron_variant	Intron 6 of 19	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.1264-4C>T		splice_region_variant, intron_variant	Intron 6 of 19	5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000879 AC: 22 AN: 250158 AF XY: 0.000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000444

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000643 AC: 94 AN: 1461362 Hom.: 0 Cov.: 31 AF XY: 0.0000757 AC XY: 55 AN XY: 727002

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000487 AC: 42 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53034

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000387 AC: 43 AN: 1111904

Other (OTH) AF: 0.000116 AC: 7 AN: 60380

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74330

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000596 Hom.: 0

Bravo AF: 0.0000378

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia type 2B Benign:1

Oct 31, 2016

Counsyl

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not specified Benign:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Multiple endocrine neoplasia type 2A Benign:1

Oct 31, 2016

Counsyl

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Multiple endocrine neoplasia, type 2 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Sep 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Mar 02, 2023

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

RET-related disorder Benign:1

Oct 22, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	12
DANN	Benign	0.86
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0018
dbscSNV1_RF	Benign	0.060
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs587780806; hg19: chr10-43606651;