rs1554818536

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020975.6(RET):​c.1402A>G​(p.Asn468Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Consequence

RET
NM_020975.6 missense

Scores

13
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.37
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RETNM_020975.6 linkuse as main transcriptc.1402A>G p.Asn468Asp missense_variant 7/20 ENST00000355710.8 NP_066124.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RETENST00000355710.8 linkuse as main transcriptc.1402A>G p.Asn468Asp missense_variant 7/205 NM_020975.6 ENSP00000347942 P4P07949-1

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
Cov.:
58
GnomAD4 genome
Cov.:
34

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Multiple endocrine neoplasia, type 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 10, 2019In 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 477315). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with aspartic acid at codon 468 of the RET protein (p.Asn468Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.26
BayesDel_addAF
Benign
-0.0091
T
BayesDel_noAF
Benign
-0.25
CADD
Uncertain
23
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.73
D;.
Eigen
Uncertain
0.21
Eigen_PC
Benign
0.14
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.83
T;T
M_CAP
Uncertain
0.088
D
MetaRNN
Uncertain
0.73
D;D
MetaSVM
Uncertain
0.12
D
MutationAssessor
Uncertain
2.5
M;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.48
T
PROVEAN
Uncertain
-2.6
D;D
REVEL
Uncertain
0.38
Sift
Uncertain
0.012
D;D
Sift4G
Uncertain
0.032
D;D
Polyphen
0.90
P;P
Vest4
0.67
MutPred
0.47
Gain of ubiquitination at K471 (P = 0.041);Gain of ubiquitination at K471 (P = 0.041);
MVP
0.89
MPC
0.41
ClinPred
0.95
D
GERP RS
4.6
Varity_R
0.75
gMVP
0.75

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.

Other links and lift over

dbSNP: rs1554818536; hg19: chr10-43606793; API