rs1309896929

Positions:

• chr10-43077304-C-G
• chr10-43077304-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020975.6(RET):​c.46C>G​(p.Leu16Val) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 35)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.305

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]

ACMG classification

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=0.15646023).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RET	NM_020975.6	c.46C>G	p.Leu16Val	missense_variant	1/20	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.46C>G	p.Leu16Val	missense_variant	1/20	5	NM_020975.6	ENSP00000347942	P4

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 35

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2023

The p.L16V variant (also known as c.46C>G), located in coding exon 1 of the RET gene, results from a C to G substitution at nucleotide position 46. The leucine at codon 16 is replaced by valine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. 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	Benign	0.079
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.39	T;.;T;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.49	T;T;T;T
M_CAP	Pathogenic	0.57	D
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	0.0	N;.;.;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.12	N;.;N;N
REVEL	Benign	0.21
Sift	Benign	0.13	T;.;T;T
Sift4G	Benign	0.21	T;T;T;T
Polyphen		0.011	B;.;.;B
Vest4		0.31
MutPred		0.31		Gain of methylation at R12 (P = 0.1347);Gain of methylation at R12 (P = 0.1347);Gain of methylation at R12 (P = 0.1347);Gain of methylation at R12 (P = 0.1347);
MVP		0.71
MPC		0.76
ClinPred		0.064	T
GERP RS		0.99
Varity_R		0.056
gMVP		0.68

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: chr10-43572752;