rs377767402

chr10-43113663-G-Achr10-43113663-G-Cchr10-43113663-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4BP6

The NM_020975.6(RET):c.1867G>A(p.Glu623Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,194 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 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

RET
NM_020975.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 5.31

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 0 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_020975.6

BP4

Computational evidence support a benign effect (MetaRNN=0.3009891).

BP6

Variant 10-43113663-G-A is Benign according to our data. Variant chr10-43113663-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 24906.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6 linkuse as main transcript	c.1867G>A	p.Glu623Lys	missense_variant	10/20	ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8 linkuse as main transcript	c.1867G>A	p.Glu623Lys	missense_variant	10/20	5	NM_020975.6	P4	P07949-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000241

AC:

AN:

248886

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134780

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000164

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000476

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461060

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726758

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74312

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

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:

0.0000712

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Multiple endocrine neoplasia, type 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 623 of the RET protein (p.Glu623Lys). This variant is present in population databases (rs377767402, gnomAD 0.02%). This missense change has been observed in individual(s) with medullary thyroid cancer (PMID: 15858153). ClinVar contains an entry for this variant (Variation ID: 24906). 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. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 05, 2021

Observed in a family with medullary thyroid carcinoma but did not segregate with disease, indicating that this variant is unlikely to be associated with increased risk for Multiple Endocrine Neoplasia type 2/Familial Medullary Thyroid Carcinoma (Ahmed 2005); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9068588, 15858153, 16849421, 14633923, 32284345) -

Multiple endocrine neoplasia type 2A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2016

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

0.11

BayesDel_addAF

Uncertain

0.036

BayesDel_noAF

Uncertain

0.080

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.44

T;T;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.30

T;T;T

MetaSVM

Pathogenic

0.90

MutationAssessor

Uncertain

2.4

M;.;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.1

N;N;N

REVEL

Uncertain

0.45

Sift

Benign

0.11

T;D;T

Sift4G

Benign

0.17

T;D;T

Polyphen

0.94

P;.;D

Vest4

0.50

MutPred

0.48

Gain of ubiquitination at E623 (P = 0.0155);.;Gain of ubiquitination at E623 (P = 0.0155);

MVP

0.79

MPC

0.31

ClinPred

0.26

GERP RS

4.9

Varity_R

0.096

gMVP

0.73

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