chr10-43126720-A-G

Position:

chr10-43126720-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PP3_ModeratePP5

The NM_020975.6(RET):c.3185A>G(p.Tyr1062Cys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,613,712 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).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

RET
NM_020975.6 missense, splice_region

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:5O:1

Conservation

PhyloP100: 9.29

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:

RET (HGNC:):

RET links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1

In a modified_residue Phosphotyrosine; by autocatalysis (size 0) in uniprot entity RET_HUMAN

PP3

MetaRNN computational evidence supports a deleterious effect, 0.934

PP5

Variant 10-43126720-A-G is Pathogenic according to our data. Variant chr10-43126720-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135181.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=5, not_provided=1, Pathogenic=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RET	NM_020975.6 linkuse as main transcript	c.3185A>G	p.Tyr1062Cys	missense_variant, splice_region_variant	19/20	ENST00000355710.8	NP_066124.1	P07949-1A0A024R7T2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8 linkuse as main transcript	c.3185A>G	p.Tyr1062Cys	missense_variant, splice_region_variant	19/20	5	NM_020975.6	ENSP00000347942.3		P07949-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250878

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135676

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000212

AC:

AN:

1461698

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

727122

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000234

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152014

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74236

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000688

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:5Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 13, 2024	Identified in individuals with Hirschsprung disease, most of whom were found to inherit the variant from an unaffected parent (PMID: 15834508, 17108762, 21475823, 22174939, 21995290); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate decreased RET and ERK phosphorylation (PMID: 26395553); This variant is associated with the following publications: (PMID: 24728327, 21475823, 17108762, 15834508, 21995290, 22174939, 24336963, 14633923, 26206375, 11061555, 31666091, 26395553) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 27, 2020

The p.Y1062C pathogenic mutation (also known as c.3185A>G), located in coding exon 19 of the RET gene, results from an A to G substitution at nucleotide position 3185. The tyrosine at codon 1062 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. This alteration has been reported in multiple individuals from unique cohorts of Hirschsprung disease patients (Wu TT et al. J Hum Genet, 2005 Apr;50:168-174; Ruiz-Ferrer M et al. Genet Med, 2006 Nov;8:704-10; Núñez-Torres R et al. BMC Med Genet, 2011 Oct;12:138; So MT et al. PLoS One, 2011 Dec;6:e28986; Jiang Q et al. Orphanet J Rare Dis, 2019 10;14:237). Further, functional analysis using western blotting showed that this alteration resulted in lower activation (phosphorylation levels) of RET and reduced ERK activation (Widowati T et al. Eur J Hum Genet, 2016 06;24:823-9). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is pathogenic for Hirschsprung disease; however, the association of this alteration with MEN2 is unknown. -

Multiple endocrine neoplasia type 2B

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Dec 13, 2015

- -

Multiple endocrine neoplasia type 2A

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Dec 13, 2015

- -

Hirschsprung disease, susceptibility to, 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 05, 2024

- -

Multiple endocrine neoplasia, type 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1062 of the RET protein (p.Tyr1062Cys). This variant is present in population databases (rs587778659, gnomAD 0.005%). This missense change has been observed in individual(s) with Hirschsprung disease (PMID: 15834508, 21995290, 22174939). ClinVar contains an entry for this variant (Variation ID: 135181). 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. Experimental studies have shown that this missense change affects RET function (PMID: 26395553). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.85

D;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Pathogenic

0.81

MutationAssessor

Benign

0.55

N;N

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-4.4

D;D

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

1.0

D;D

Vest4

0.97

MutPred

0.80

Loss of phosphorylation at Y1062 (P = 0.013);Loss of phosphorylation at Y1062 (P = 0.013);

MVP

0.97

MPC

0.71

ClinPred

0.99

GERP RS

5.0

Varity_R

0.50

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.31

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.31

Position offset: 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