rs1564480827

Variant names:

• chr10-43077265-A-G
• rs1564480827
• NM_020975.6:c.7A>G

Variant summary

Our verdict is Uncertain significance. The variant received 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. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K3R) has been classified 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
• Publications: 0 publications found

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]

RET Gene-Disease associations (from GenCC):

• familial medullary thyroid carcinoma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• multiple endocrine neoplasia type 2A

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
• multiple endocrine neoplasia type 2B

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Hirschsprung disease, susceptibility to, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Haddad syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Hirschsprung disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• renal agenesis, unilateral

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• bilateral renal agenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• renal agenesis

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ENSG00000303432 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 rank	MANE	Protein	UniProt
RET	NM_020975.6	c.7A>G	p.Lys3Glu	missense_variant	Exon 1 of 20	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.7A>G	p.Lys3Glu	missense_variant	Exon 1 of 20	5	NM_020975.6	ENSP00000347942.3

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

African (AFR) AF: 0.00 AC: 0 AN: 28140

American (AMR) AF: 0.00 AC: 0 AN: 32740

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24222

East Asian (EAS) AF: 0.00 AC: 0 AN: 32618

South Asian (SAS) AF: 0.00 AC: 0 AN: 76044

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4852

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1064366

Other (OTH) AF: 0.00 AC: 0 AN: 56432

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

Aug 06, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hereditary cancer-predisposing syndrome Uncertain:2

Aug 01, 2018

GeneKor MSA

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Based on the available evidence, the clinical significance of this variant remains unclear. -

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
PhyloP100		0.79
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
PromoterAI		0.14	Neutral
Varity_R		0.082
gMVP		0.60
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs1564480827; hg19: chr10-43572713;