chr10-43119566-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_020975.6(RET):​c.2428G>A​(p.Gly810Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,457,110 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G810C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

RET
NM_020975.6 missense

Scores

14
4
1

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 9.99
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.983

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RETNM_020975.6 linkuse as main transcriptc.2428G>A p.Gly810Ser missense_variant 14/20 ENST00000355710.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RETENST00000355710.8 linkuse as main transcriptc.2428G>A p.Gly810Ser missense_variant 14/205 NM_020975.6 P4P07949-1

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD3 exomes
AF:
0.00000418
AC:
1
AN:
239128
Hom.:
0
AF XY:
0.00000762
AC XY:
1
AN XY:
131154
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000330
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000275
AC:
4
AN:
1457110
Hom.:
0
Cov.:
33
AF XY:
0.00000276
AC XY:
2
AN XY:
724894
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.0000333
GnomAD4 genome
Cov.:
34
Bravo
AF:
0.00000378
ExAC
AF:
0.00000826
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Multiple endocrine neoplasia, type 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 05, 2023This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 810 of the RET protein (p.Gly810Ser). This variant is present in population databases (rs764784013, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 543739). 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. -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 11, 2023The p.G810S variant (also known as c.2428G>A), located in coding exon 14 of the RET gene, results from a G to A substitution at nucleotide position 2428. The glycine at codon 810 is replaced by serine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.72
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.44
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.92
D;.
Eigen
Pathogenic
0.77
Eigen_PC
Pathogenic
0.67
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Uncertain
0.22
D
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Pathogenic
0.91
D
MutationAssessor
Uncertain
2.8
M;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.77
T
PROVEAN
Pathogenic
-5.8
D;D
REVEL
Pathogenic
0.80
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;D
Vest4
0.93
MutPred
0.93
Loss of catalytic residue at G810 (P = 0.0329);Loss of catalytic residue at G810 (P = 0.0329);
MVP
0.94
MPC
0.78
ClinPred
1.0
D
GERP RS
5.4
Varity_R
0.97
gMVP
0.87

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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.

Other links and lift over

dbSNP: rs764784013; hg19: chr10-43615014; API