rs1799939

chr10-43114671-G-Achr10-43114671-G-Cchr10-43114671-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_020975.6(RET):c.2071G>A(p.Gly691Ser) variant causes a missense change. The variant allele was found at a frequency of 0.184 in 1,612,242 control chromosomes in the GnomAD database, including 29,287 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G691C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.17 ( 2471 hom., cov: 31)

Exomes 𝑓: 0.19 ( 26816 hom. )

Consequence

RET
NM_020975.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:21O:1

Conservation

PhyloP100: 4.41

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005253911).

BP6

Variant 10-43114671-G-A is Benign according to our data. Variant chr10-43114671-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 24934.We mark this variant Likely_benign, oryginal submissions are: {Benign=13, not_provided=1, Likely_benign=4, Uncertain_significance=1}. Variant chr10-43114671-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.242 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6 linkuse as main transcript	c.2071G>A	p.Gly691Ser	missense_variant	11/20	ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8 linkuse as main transcript	c.2071G>A	p.Gly691Ser	missense_variant	11/20	5	NM_020975.6	P4	P07949-1

Frequencies

GnomAD3 genomes

AF:

0.170

AC:

25745

AN:

151742

Hom.:

2472

Cov.:

show subpopulations

Gnomad AFR

AF:

0.101

Gnomad AMI

AF:

0.158

Gnomad AMR

AF:

0.248

Gnomad ASJ

AF:

0.202

Gnomad EAS

AF:

0.105

Gnomad SAS

AF:

0.243

Gnomad FIN

AF:

0.230

Gnomad MID

AF:

0.255

Gnomad NFE

AF:

0.182

Gnomad OTH

AF:

0.182

GnomAD3 exomes

AF:

0.210

AC:

52572

AN:

250098

Hom.:

6336

AF XY:

0.208

AC XY:

28214

AN XY:

135328

show subpopulations

Gnomad AFR exome

AF:

0.0983

Gnomad AMR exome

AF:

0.354

Gnomad ASJ exome

AF:

0.195

Gnomad EAS exome

AF:

0.116

Gnomad SAS exome

AF:

0.255

Gnomad FIN exome

AF:

0.218

Gnomad NFE exome

AF:

0.185

Gnomad OTH exome

AF:

0.220

GnomAD4 exome

AF:

0.185

AC:

270502

AN:

1460382

Hom.:

26816

Cov.:

AF XY:

0.187

AC XY:

135943

AN XY:

726526

show subpopulations

Gnomad4 AFR exome

AF:

0.0963

Gnomad4 AMR exome

AF:

0.338

Gnomad4 ASJ exome

AF:

0.199

Gnomad4 EAS exome

AF:

0.0943

Gnomad4 SAS exome

AF:

0.257

Gnomad4 FIN exome

AF:

0.212

Gnomad4 NFE exome

AF:

0.178

Gnomad4 OTH exome

AF:

0.180

GnomAD4 genome

AF:

0.170

AC:

25747

AN:

151860

Hom.:

2471

Cov.:

AF XY:

0.173

AC XY:

12841

AN XY:

74188

show subpopulations

Gnomad4 AFR

AF:

0.101

Gnomad4 AMR

AF:

0.248

Gnomad4 ASJ

AF:

0.202

Gnomad4 EAS

AF:

0.105

Gnomad4 SAS

AF:

0.243

Gnomad4 FIN

AF:

0.230

Gnomad4 NFE

AF:

0.182

Gnomad4 OTH

AF:

0.179

Alfa

AF:

0.180

Hom.:

3497

Bravo

AF:

0.170

TwinsUK

AF:

0.182

AC:

674

ALSPAC

AF:

0.181

AC:

699

ESP6500AA

AF:

0.103

AC:

455

ESP6500EA

AF:

0.185

AC:

1587

ExAC

AF:

0.202

AC:

24557

Asia WGS

AF:

0.169

AC:

586

AN:

3478

EpiCase

AF:

0.189

EpiControl

AF:

0.194

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:21Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:8Other:1

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Dec 10, 2020	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 31, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 11, 2013	Gly691Ser in exon 11 of RET: This variant is not expected to have clinical signi ficance because it has been identified in 21% (276/1321) chromosomes from a broa d, though clinically and racially unspecified population (dbSNP rs1799939). -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Multiple endocrine neoplasia, type 2

Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -

not provided

Benign:3

Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 01, 2017	- -

Multiple endocrine neoplasia type 2A

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	Aug 06, 2019	- -

Multiple endocrine neoplasia type 2B

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Pheochromocytoma

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hirschsprung disease, susceptibility to, 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Renal hypodysplasia/aplasia 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Multiple endocrine neoplasia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 19, 2014

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.43

Cadd

Benign

Dann

Benign

0.86

DEOGEN2

Uncertain

0.42

T;.

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.84

T;T

MetaRNN

Benign

0.0053

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

N;N

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.95

N;N

REVEL

Benign

0.21

Sift

Benign

0.18

T;T

Sift4G

Benign

0.12

T;T

Polyphen

0.062

B;B

Vest4

0.045

MPC

0.20

ClinPred

0.015

GERP RS

-1.1

Varity_R

0.039

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over