rs376465385

chr10-43109149-C-Gchr10-43109149-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1_Moderate PM1 PM2 PP3_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. Synonymous variant affecting the same amino acid position (i.e. N394N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0460

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 Pathogenic. Variant got 10 ACMG points.

• PS1: Transcript NM_020975.6 (RET) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity RET_HUMAN
• 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	UniProt
RET	NM_020975.6	c.1182C>G	p.Asn394Lys	missense_variant	6/20	ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8	c.1182C>G	p.Asn394Lys	missense_variant	6/20	5	NM_020975.6	P4

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

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2022

The 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;