chr10-43100733-C-T

Variant names:

• chr10-43100733-C-T
• rs754967305
• NM_020975.6:c.337+11C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_020975.6(RET):​c.337+11C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000733 in 1,581,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: RET NM_020975.6 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.15
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BP6: Variant 10-43100733-C-T is Benign according to our data. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43100733-C-T is described in CliVar as Likely_benign. Clinvar id is 548834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6	c.337+11C>T		intron_variant	Intron 2 of 19	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.337+11C>T		intron_variant	Intron 2 of 19	5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000312 AC: 6 AN: 192570 AF XY: 0.0000385

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000346

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000619

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000706 AC: 101 AN: 1429624 Hom.: 0 Cov.: 43 AF XY: 0.0000720 AC XY: 51 AN XY: 708008

African (AFR) AF: 0.00 AC: 0 AN: 33024

American (AMR) AF: 0.0000747 AC: 3 AN: 40174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25456

East Asian (EAS) AF: 0.0000260 AC: 1 AN: 38504

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 82132

European-Finnish (FIN) AF: 0.0000201 AC: 1 AN: 49700

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4602

European-Non Finnish (NFE) AF: 0.0000775 AC: 85 AN: 1096942

Other (OTH) AF: 0.000169 AC: 10 AN: 59090

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74322

African (AFR) AF: 0.0000965 AC: 4 AN: 41450

American (AMR) AF: 0.000327 AC: 5 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68030

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000196

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 19, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 30, 2016

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Oct 23, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: RET c.337+11C>T alters a non-conserved nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.1e-05 in 192570 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.337+11C>T in individuals affected with Multiple Endocrine Neoplasia Type 2 and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Multiple endocrine neoplasia type 2A Benign:1

Jan 03, 2018

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.014
DANN	Benign	0.74
PhyloP100		-2.1
PromoterAI		-0.057	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs754967305; hg19: chr10-43596181;