10-43077265-A-G

Variant summary

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

The NM_020975.6(RET):c.7A>G(p.Lys3Glu) 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)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 0.792

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=0.25183904).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6	c.7A>G	p.Lys3Glu	missense_variant	1/20	ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8	c.7A>G	p.Lys3Glu	missense_variant	1/20	5	NM_020975.6	P4

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1352642 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 667142

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 35

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 16, 2023	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 3 of the RET protein (p.Lys3Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with RET-related conditions (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 584566). 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 tolerated. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	May 31, 2023	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 24, 2021	The p.K3E variant (also known as c.7A>G), located in coding exon 1 of the RET gene, results from an A to G substitution at nucleotide position 7. The lysine at codon 3 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been reported as variant of uncertain significance in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is well conserved in available vertebrate species. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
Cadd	Benign	21
Dann	Benign	0.96
DEOGEN2	Benign	0.39	T;.;T;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.45	T;T;T;T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	0.69	N;.;.;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.050	N;.;N;N
REVEL	Benign	0.16
Sift	Uncertain	0.025	D;.;D;D
Sift4G	Uncertain	0.039	D;T;T;D
Polyphen		0.015	B;.;.;B
Vest4		0.22
MutPred		0.16		Loss of ubiquitination at K3 (P = 0.0326);Loss of ubiquitination at K3 (P = 0.0326);Loss of ubiquitination at K3 (P = 0.0326);Loss of ubiquitination at K3 (P = 0.0326);
MVP		0.61
MPC		1.4
ClinPred		0.14	T
GERP RS		1.8
Varity_R		0.082
gMVP		0.60

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

Other links and lift over

dbSNP: rs1564480827; hg19: chr10-43572713;