rs878855063

chr10-43128125-GA-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_020975.6(RET):c.3203del(p.Asn1068ThrfsTer41) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. N1068N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RET NM_020975.6 frameshift
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.91

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.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0428 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• 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.3203del	p.Asn1068ThrfsTer41	frameshift_variant	20/20	ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8	c.3203del	p.Asn1068ThrfsTer41	frameshift_variant	20/20	5	NM_020975.6	P4
RET	ENST00000615310.5	c.*1373del		3_prime_UTR_variant	17/17	5
RET	ENST00000683007.1	n.4166del		non_coding_transcript_exon_variant	16/16

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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 05, 2016

This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a RET-related disease. Experimental studies have not been published for this variant, and the functional effect of this truncation is unknown. In summary, this is a novel truncation in the last exon of RET, with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. This sequence change deletes 1 nucleotide from exon 20 of the RET mRNA (c.3203delA), causing a frameshift at codon 1068. This creates a premature translational stop signal in the last exon of the RET mRNA (p.Asn1068Thrfs*41). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated RET protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs878855063; hg19: chr10-43623573;