rs377767441

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020975.6(RET):​c.2098A>C​(p.Met700Leu) 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 benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M700I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Consequence

RET
NM_020975.6 missense

Scores

3
16

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.94
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.14862359).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RETNM_020975.6 linkuse as main transcriptc.2098A>C p.Met700Leu missense_variant 11/20 ENST00000355710.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RETENST00000355710.8 linkuse as main transcriptc.2098A>C p.Met700Leu missense_variant 11/205 NM_020975.6 P4P07949-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Uncertain
0.055
T
BayesDel_noAF
Benign
-0.16
CADD
Benign
15
DANN
Benign
0.72
DEOGEN2
Benign
0.36
T;.
Eigen
Benign
-0.69
Eigen_PC
Benign
-0.54
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Benign
0.72
T;T
M_CAP
Benign
0.039
D
MetaRNN
Benign
0.15
T;T
MetaSVM
Benign
-0.72
T
MutationAssessor
Benign
0.90
L;L
MutationTaster
Benign
0.85
D;D
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-0.20
N;N
REVEL
Uncertain
0.31
Sift
Benign
0.48
T;T
Sift4G
Benign
1.0
T;T
Polyphen
0.0010
B;B
Vest4
0.30
MutPred
0.20
Loss of disorder (P = 0.1504);Loss of disorder (P = 0.1504);
MVP
0.76
MPC
0.19
ClinPred
0.44
T
GERP RS
-0.12
Varity_R
0.13
gMVP
0.37

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: chr10-43610146; API