rs2742236

chr10-43125103-G-A

Variant summary

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

The NM_020975.6(RET):c.3039+121G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.541 in 883,598 control chromosomes in the GnomAD database, including 133,351 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 0.56 (24258 hom., cov: 31)
  • Exomes 𝑓: 0.54 (109093 hom.)
• Consequence: RET NM_020975.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.388

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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.615 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6	c.3039+121G>A		intron_variant		ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8	c.3039+121G>A		intron_variant		5	NM_020975.6	P4

Frequencies

GnomAD3 genomes AF: 0.559 AC: 84762 AN: 151720 Hom.: 24228 Cov.: 31

Gnomad AFR AF: 0.621

Gnomad AMI AF: 0.651

Gnomad AMR AF: 0.499

Gnomad ASJ AF: 0.504

Gnomad EAS AF: 0.291

Gnomad SAS AF: 0.312

Gnomad FIN AF: 0.525

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.580

Gnomad OTH AF: 0.535

GnomAD4 exome AF: 0.537 AC: 393082 AN: 731760 Hom.: 109093 AF XY: 0.528 AC XY: 203232 AN XY: 384990

Gnomad4 AFR exome AF: 0.618

Gnomad4 AMR exome AF: 0.430

Gnomad4 ASJ exome AF: 0.514

Gnomad4 EAS exome AF: 0.285

Gnomad4 SAS exome AF: 0.333

Gnomad4 FIN exome AF: 0.530

Gnomad4 NFE exome AF: 0.589

Gnomad4 OTH exome AF: 0.541

GnomAD4 genome AF: 0.559 AC: 84842 AN: 151838 Hom.: 24258 Cov.: 31 AF XY: 0.551 AC XY: 40885 AN XY: 74190

Gnomad4 AFR AF: 0.621

Gnomad4 AMR AF: 0.499

Gnomad4 ASJ AF: 0.504

Gnomad4 EAS AF: 0.291

Gnomad4 SAS AF: 0.313

Gnomad4 FIN AF: 0.525

Gnomad4 NFE AF: 0.580

Gnomad4 OTH AF: 0.538

Alfa AF: 0.533 Hom.: 4573

Bravo AF: 0.563

Asia WGS AF: 0.336 AC: 1173 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	1.8
Dann	Benign	0.41

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: rs2742236; hg19: chr10-43620551; COSMIC: COSV60691630;