rs2251674

chr10-43109944-G-Achr10-43109944-G-C

Variant summary

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

The NM_020975.6(RET):c.1263+714G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.758 in 152,120 control chromosomes in the GnomAD database, including 44,232 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 0.76 (44232 hom., cov: 33)
• Consequence: RET NM_020975.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.34

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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.847 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6	c.1263+714G>A		intron_variant		ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8	c.1263+714G>A		intron_variant		5	NM_020975.6	P4

Frequencies

GnomAD3 genomes AF: 0.758 AC: 115199 AN: 152002 Hom.: 44179 Cov.: 33

Gnomad AFR AF: 0.854

Gnomad AMI AF: 0.834

Gnomad AMR AF: 0.749

Gnomad ASJ AF: 0.711

Gnomad EAS AF: 0.543

Gnomad SAS AF: 0.708

Gnomad FIN AF: 0.636

Gnomad MID AF: 0.731

Gnomad NFE AF: 0.742

Gnomad OTH AF: 0.748

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

GnomAD4 genome AF: 0.758 AC: 115316 AN: 152120 Hom.: 44232 Cov.: 33 AF XY: 0.752 AC XY: 55897 AN XY: 74348

Gnomad4 AFR AF: 0.854

Gnomad4 AMR AF: 0.749

Gnomad4 ASJ AF: 0.711

Gnomad4 EAS AF: 0.543

Gnomad4 SAS AF: 0.709

Gnomad4 FIN AF: 0.636

Gnomad4 NFE AF: 0.742

Gnomad4 OTH AF: 0.748

Alfa AF: 0.747 Hom.: 12636

Bravo AF: 0.772

Asia WGS AF: 0.638 AC: 2222 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.48
Dann	Benign	0.58

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: rs2251674; hg19: chr10-43605392; COSMIC: COSV60686041; COSMIC: COSV60686041;