10-43123745-G-T

Position:

• chr10-43123745-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_020975.6(RET):​c.2876G>T​(p.Arg959Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.14

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RET	NM_020975.6	c.2876G>T	p.Arg959Leu	missense_variant	17/20	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.2876G>T	p.Arg959Leu	missense_variant	17/20	5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461850 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727218

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

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.: 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

Sep 19, 2024

The p.R959L variant (also known as c.2876G>T), located in coding exon 17 of the RET gene, results from a G to T substitution at nucleotide position 2876. The arginine at codon 959 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. 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	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.90	D;D
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	0.69	N;N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.9	D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.026	D;D
Polyphen		1.0	D;D
Vest4		0.90
MutPred		0.67		Loss of disorder (P = 0.1);Loss of disorder (P = 0.1);
MVP		0.97
MPC		0.83
ClinPred		1.0	D
GERP RS		4.4
Varity_R		0.95
gMVP		0.91

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: chr10-43619193;