10-43077289-C-T

Variant names:

• chr10-43077289-C-T
• rs587780812
• NM_020975.6:c.31C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_020975.6(RET):​c.31C>T​(p.Leu11Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000662 in 1,509,608 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 35)
  • Exomes 𝑓: 0.0000052 (0 hom.)
• Consequence: RET NM_020975.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 1.05
• Publications: 3 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

ENSG00000303432 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 10-43077289-C-T is Benign according to our data. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368. Variant chr10-43077289-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 477368.
• BP7: Synonymous conserved (PhyloP=1.05 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6	c.31C>T	p.Leu11Leu	synonymous_variant	Exon 1 of 20	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.31C>T	p.Leu11Leu	synonymous_variant	Exon 1 of 20	5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151804 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000480

GnomAD4 exome AF: 0.00000516 AC: 7 AN: 1357804 Hom.: 0 Cov.: 30 AF XY: 0.00000747 AC XY: 5 AN XY: 669706

African (AFR) AF: 0.0000349 AC: 1 AN: 28622

American (AMR) AF: 0.00 AC: 0 AN: 33244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24370

East Asian (EAS) AF: 0.00 AC: 0 AN: 33246

South Asian (SAS) AF: 0.00 AC: 0 AN: 76410

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33296

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5070

European-Non Finnish (NFE) AF: 0.00000469 AC: 5 AN: 1066830

Other (OTH) AF: 0.0000176 AC: 1 AN: 56716

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151804 Hom.: 0 Cov.: 35 AF XY: 0.0000405 AC XY: 3 AN XY: 74160

African (AFR) AF: 0.00 AC: 0 AN: 41358

American (AMR) AF: 0.00 AC: 0 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10512

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67902

Other (OTH) AF: 0.000480 AC: 1 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Multiple endocrine neoplasia, type 2 Benign:2

Dec 07, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Dec 31, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this variant does not alter splicing; Has not been previously published as pathogenic or benign to our knowledge -

Multiple endocrine neoplasia type 2A;C0025269:Multiple endocrine neoplasia type 2B;C0031511:Pheochromocytoma;C1833921:Familial medullary thyroid carcinoma;C3888239:Hirschsprung disease, susceptibility to, 1 Benign:1

Apr 29, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Feb 23, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	14
DANN	Benign	0.96
PhyloP100		1.1
PromoterAI		0.020	Neutral

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: rs587780812; hg19: chr10-43572737;