rs77702891

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_020975.6(RET):c.938G>A(p.Arg313Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,613,324 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

RET
NM_020975.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7O:1

Conservation

PhyloP100: 2.39

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.22862077).

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000287 (42/1461150) while in subpopulation AMR AF= 0.000627 (28/44666). AF 95% confidence interval is 0.000445. There are 0 homozygotes in gnomad4_exome. There are 18 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6 link	c.938G>A	p.Arg313Gln	missense_variant	Exon 5 of 20	ENST00000355710.8	NP_066124.1	P07949-1A0A024R7T2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8 link	c.938G>A	p.Arg313Gln	missense_variant	Exon 5 of 20	5	NM_020975.6	ENSP00000347942.3		P07949-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000121

AC:

AN:

248534

Hom.:

AF XY:

0.000111

AC XY:

AN XY:

134798

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000756

Gnomad ASJ exome

AF:

0.0000997

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000287

AC:

AN:

1461150

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

726842

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000627

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000422

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.0000989

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Multiple endocrine neoplasia type 2A

Uncertain:2

Apr 18, 2023

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

Jul 27, 2017

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:2

Oct 28, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Also reported in a patient with short segment Hirschsprung disease, but it is unknown whether this individual was screened for variants in other genes associated with this phenotype (So et al., 2011); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in the homozygous state in a patient with total colonic aganglionosis with small bowel involvement who underwent targeted testing of the RET gene; both parents of this individual were heterozygous for this variant and were reportedly healthy (Seri et al., 1997); This variant is associated with the following publications: (PMID: 21995290, 9090527, 22174939) -

Dec 03, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RET c.938G>A (p.Arg313Gln) variant has been reported in the published literature in individuals affected with pheochromocytoma (PMID: 29315604 (2018)) and biliary tract cancer (PMID: 35958441 (2022)). In addition, it was identified in individuals affected with Hirschsprung disease (PMID: 22174939 (2011), 23441071 (2013)) and in a homozygous child with a severe phenotype (PMID: 9090527 (1997)). A related variant affecting the same codon, c.937C>T (p.Arg313Trp), has also been reported in an individual with Hirschsprung disease (PMID: 21995290 (2011)). The frequency of the c.938G>A variant in the general population, 0.00076 (26/34410 chromosomes in Admixed American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

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

Uncertain:1

Mar 19, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Multiple endocrine neoplasia, type 2

Uncertain:1

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 313 of the RET protein (p.Arg313Gln). This variant is present in population databases (rs77702891, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Hirschsprung disease (PMID: 9090527, 22174939, 29315604). ClinVar contains an entry for this variant (Variation ID: 13932). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Dec 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R313Q variant (also known as c.938G>A), located in coding exon 5 of the RET gene, results from a G to A substitution at nucleotide position 938. The arginine at codon 313 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been reported in a homozygous state in a child born to consanguineous parents with the most severe Hirschsprung disease phenotype (total colonic aganglionosis with small bowel involvement) (Seri M et al. Hum. Mutat. 1997;9:243-9). This alteration has also been reported in a cohort of 601 Chinese Hirschsprung disease patients (So MT et al. PLoS One. 2011 Dec;6:e28986). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a multiple endocrine neoplasia type 2 (MEN2) disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). Based on the supporting evidence, the association of this alteration with Hirschsprung disease is unknown; however, the association of this alteration with MEN2 is unlikely. -

Hirschsprung disease, susceptibility to, 1

Other:1

Jan 01, 1997

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Uncertain

0.0

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

T;.;.

Eigen

Benign

0.074

Eigen_PC

Benign

0.066

FATHMM_MKL

Benign

0.34

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.23

T;T;T

MetaSVM

Benign

-0.61

MutationAssessor

Uncertain

2.4

M;.;M

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.65

N;.;N

REVEL

Uncertain

0.55

Sift

Uncertain

0.017

D;.;D

Sift4G

Benign

0.12

T;D;T

Polyphen

0.94

P;.;D

Vest4

0.45

MutPred

0.72

Gain of sheet (P = 0.0049);Gain of sheet (P = 0.0049);Gain of sheet (P = 0.0049);

MVP

0.93

MPC

0.31

ClinPred

0.16

GERP RS

2.2

Varity_R

0.27

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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