rs376465385

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS1_ModeratePM2PP3_Strong

The NM_020975.6(RET):​c.1182C>G​(p.Asn394Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: not found (cov: 33)

Consequence

RET
NM_020975.6 missense

Scores

2
11
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0460
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 Likely_pathogenic. Variant got 8 ACMG points.

PS1
Transcript NM_020975.6 (RET) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RETNM_020975.6 linkuse as main transcriptc.1182C>G p.Asn394Lys missense_variant 6/20 ENST00000355710.8 NP_066124.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RETENST00000355710.8 linkuse as main transcriptc.1182C>G p.Asn394Lys missense_variant 6/205 NM_020975.6 ENSP00000347942 P4P07949-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
33

ClinVar

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

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 12, 2022The p.N394K variant (also known as c.1182C>G), located in coding exon 6 of the RET gene, results from a C to G substitution at nucleotide position 1182. The asparagine at codon 394 is replaced by lysine, an amino acid with similar properties. This alteration was identified in an individual with Hirschsprung disease (Bolk S et al. Proc Natl Acad Sci U S A, 2000 Jan;97:268-73). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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
Uncertain
0.49
BayesDel_addAF
Benign
-0.015
T
BayesDel_noAF
Benign
-0.26
CADD
Benign
13
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.75
D;.;.
Eigen
Benign
-0.14
Eigen_PC
Benign
-0.28
FATHMM_MKL
Benign
0.64
D
LIST_S2
Uncertain
0.93
D;D;D
M_CAP
Pathogenic
0.32
D
MetaRNN
Pathogenic
0.97
D;D;D
MetaSVM
Uncertain
-0.075
T
MutationAssessor
Uncertain
2.7
M;.;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.68
T
PROVEAN
Uncertain
-2.8
D;.;D
REVEL
Uncertain
0.55
Sift
Uncertain
0.0040
D;.;D
Sift4G
Uncertain
0.010
D;D;D
Polyphen
1.0
D;.;D
Vest4
0.90
MutPred
0.89
Gain of methylation at N394 (P = 0.0168);Gain of methylation at N394 (P = 0.0168);Gain of methylation at N394 (P = 0.0168);
MVP
0.82
MPC
0.43
ClinPred
0.99
D
GERP RS
-2.6
Varity_R
0.81
gMVP
0.93

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-43604597; API