10-43127485-T-C

Position:

• chr10-43127485-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000340058.6(RET):​c.*731T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.827 in 1,032,618 control chromosomes in the GnomAD database, including 355,142 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.84 (54289 hom., cov: 32)
  • Exomes 𝑓: 0.83 (300853 hom.)
• Consequence: RET ENST00000340058.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0820

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.938 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6	c.3188-627T>C		intron_variant		ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8	c.3188-627T>C		intron_variant		5	NM_020975.6	P4

Frequencies

GnomAD3 genomes AF: 0.839 AC: 127638 AN: 152064 Hom.: 54222 Cov.: 32

Gnomad AFR AF: 0.946

Gnomad AMI AF: 0.920

Gnomad AMR AF: 0.808

Gnomad ASJ AF: 0.765

Gnomad EAS AF: 0.500

Gnomad SAS AF: 0.710

Gnomad FIN AF: 0.822

Gnomad MID AF: 0.788

Gnomad NFE AF: 0.823

Gnomad OTH AF: 0.825

GnomAD4 exome AF: 0.825 AC: 726423 AN: 880436 Hom.: 300853 Cov.: 26 AF XY: 0.825 AC XY: 335428 AN XY: 406822

Gnomad4 AFR exome AF: 0.955

Gnomad4 AMR exome AF: 0.794

Gnomad4 ASJ exome AF: 0.771

Gnomad4 EAS exome AF: 0.485

Gnomad4 SAS exome AF: 0.746

Gnomad4 FIN exome AF: 0.833

Gnomad4 NFE exome AF: 0.831

Gnomad4 OTH exome AF: 0.799

GnomAD4 genome AF: 0.840 AC: 127769 AN: 152182 Hom.: 54289 Cov.: 32 AF XY: 0.836 AC XY: 62213 AN XY: 74412

Gnomad4 AFR AF: 0.946

Gnomad4 AMR AF: 0.808

Gnomad4 ASJ AF: 0.765

Gnomad4 EAS AF: 0.500

Gnomad4 SAS AF: 0.711

Gnomad4 FIN AF: 0.822

Gnomad4 NFE AF: 0.823

Gnomad4 OTH AF: 0.824

Alfa AF: 0.823 Hom.: 16530

Bravo AF: 0.846

Asia WGS AF: 0.624 AC: 2172 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	9.3
DANN	Benign	0.83

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

LitVar

Other links and lift over

dbSNP: rs2565200; hg19: chr10-43622933; COSMIC: COSV60689476;