rs377767394

chr10-43113603-A-Cchr10-43113603-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_020975.6(RET):c.1807A>C(p.Lys603Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,428 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.67

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 4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_020975.6
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6	c.1807A>C	p.Lys603Gln	missense_variant	10/20	ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8	c.1807A>C	p.Lys603Gln	missense_variant	10/20	5	NM_020975.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460428 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726416

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: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Multiple endocrine neoplasia, type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 20, 2022

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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RET function (PMID: 15277225). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This missense change has been observed in individual(s) with medullary thyroid cancer (PMID: 11746981, 28946813). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 603 of the RET protein (p.Lys603Gln). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Benign	16
Dann	Benign	0.96
DEOGEN2	Uncertain	0.43	T;T;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.52
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.84	T;T;T
M_CAP	Benign	0.068	D
MetaRNN	Uncertain	0.62	D;D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	1.9	L;.;L
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Uncertain	0.58
Sift	Benign	0.14	T;T;T
Sift4G	Benign	0.43	T;D;T
Polyphen		0.068	B;.;B
Vest4		0.32
MutPred		0.76		Loss of ubiquitination at K603 (P = 0.0063);.;Loss of ubiquitination at K603 (P = 0.0063);
MVP		0.98
MPC		0.30
ClinPred		0.31	T
GERP RS		2.5
Varity_R		0.34
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs377767394; hg19: chr10-43609051;