rs758298916

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_020975.6(RET):c.972G>C(p.Trp324Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,461,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. W324G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

RET
NM_020975.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:1

Conservation

PhyloP100: 5.27

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 Uncertain_significance. Variant got 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.853

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6 linkuse as main transcript	c.972G>C	p.Trp324Cys	missense_variant	5/20	ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8 linkuse as main transcript	c.972G>C	p.Trp324Cys	missense_variant	5/20	5	NM_020975.6	P4	P07949-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000321

AC:

AN:

248846

Hom.:

AF XY:

0.0000371

AC XY:

AN XY:

134950

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000598

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:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1461370

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

726962

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000459

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Multiple endocrine neoplasia type 2A

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 18, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 27, 2016	- -

Multiple endocrine neoplasia type 2B

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Oct 27, 2016

- -

Pheochromocytoma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Hirschsprung disease, susceptibility to, 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Renal hypodysplasia/aplasia 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

Multiple endocrine neoplasia, type 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 16, 2024

This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 324 of the RET protein (p.Trp324Cys). This variant is present in population databases (rs758298916, gnomAD 0.06%). This missense change has been observed in individual(s) with Hirschsprung disease (PMID: 11955539). ClinVar contains an entry for this variant (Variation ID: 188078). 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 disruptive. 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 13, 2019

Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in an individual with Hirschsprung disease (Fitze et al., 2002); This variant is associated with the following publications: (PMID: 16732321, 15956201, 11955539) -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2022

The p.W324C variant (also known as c.972G>C), located in coding exon 5 of the RET gene, results from a G to C substitution at nucleotide position 972. The tryptophan at codon 324 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in one individual from a cohort of 76 Caucasians from Germany with Hirschsprung’s disease (Fitze G et al. Lancet 2002 Apr; 359(9313):1200-5). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a 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's disease is unknown; however, the association of this alteration with MEN2 is unlikely. -

Multiple endocrine neoplasia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.22

Cadd

Pathogenic

Dann

Uncertain

0.99

DEOGEN2

Uncertain

0.74

D;.;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.85

D;D;D

MetaSVM

Uncertain

0.11

MutationAssessor

Uncertain

2.6

M;.;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-3.2

D;.;D

REVEL

Pathogenic

0.69

Sift

Uncertain

0.014

D;.;D

Sift4G

Benign

0.13

T;D;T

Polyphen

0.99

D;.;D

Vest4

0.78

MutPred

0.81

Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);

MVP

0.93

MPC

0.99

ClinPred

0.76

GERP RS

5.3

Varity_R

0.20

gMVP

0.94

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

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