rs1864400

chr10-43114918-G-Achr10-43114918-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_020975.6(RET):c.2136+182G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.824 in 152,028 control chromosomes in the GnomAD database, including 52,197 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.82 (52197 hom., cov: 30)
• Consequence: RET NM_020975.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.89

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 10-43114918-G-A is Benign according to our data. Variant chr10-43114918-G-A is described in ClinVar as [Benign]. Clinvar id is 1226080.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.9 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6	c.2136+182G>A		intron_variant		ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8	c.2136+182G>A		intron_variant		5	NM_020975.6	P4

Frequencies

GnomAD3 genomes AF: 0.824 AC: 125199 AN: 151910 Hom.: 52134 Cov.: 30

Gnomad AFR AF: 0.908

Gnomad AMI AF: 0.920

Gnomad AMR AF: 0.802

Gnomad ASJ AF: 0.768

Gnomad EAS AF: 0.497

Gnomad SAS AF: 0.708

Gnomad FIN AF: 0.814

Gnomad MID AF: 0.791

Gnomad NFE AF: 0.815

Gnomad OTH AF: 0.814

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.824 AC: 125326 AN: 152028 Hom.: 52197 Cov.: 30 AF XY: 0.822 AC XY: 61071 AN XY: 74312

Gnomad4 AFR AF: 0.908

Gnomad4 AMR AF: 0.802

Gnomad4 ASJ AF: 0.768

Gnomad4 EAS AF: 0.497

Gnomad4 SAS AF: 0.709

Gnomad4 FIN AF: 0.814

Gnomad4 NFE AF: 0.815

Gnomad4 OTH AF: 0.814

Alfa AF: 0.806 Hom.: 8537

Bravo AF: 0.830

Asia WGS AF: 0.624 AC: 2170 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.26
Dann	Benign	0.35

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: rs1864400; hg19: chr10-43610366; COSMIC: COSV60687565; COSMIC: COSV60687565;