rs3026750

Positions:

• chr10-43112308-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.1648+84G>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 1,539,160 control chromosomes in the GnomAD database, including 444,138 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 0.77 (45598 hom., cov: 35)
  • Exomes 𝑓: 0.76 (398540 hom.)
• Consequence: RET NM_020975.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.70

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.83 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RET	NM_020975.6	c.1648+84G>A		intron_variant		ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.1648+84G>A		intron_variant		5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes AF: 0.772 AC: 117002 AN: 151628 Hom.: 45538 Cov.: 35

Gnomad AFR AF: 0.837

Gnomad AMI AF: 0.819

Gnomad AMR AF: 0.760

Gnomad ASJ AF: 0.716

Gnomad EAS AF: 0.510

Gnomad SAS AF: 0.621

Gnomad FIN AF: 0.780

Gnomad MID AF: 0.728

Gnomad NFE AF: 0.767

Gnomad OTH AF: 0.750

GnomAD4 exome AF: 0.756 AC: 1048831 AN: 1387412 Hom.: 398540 AF XY: 0.752 AC XY: 514590 AN XY: 684634

Gnomad4 AFR exome AF: 0.832

Gnomad4 AMR exome AF: 0.767

Gnomad4 ASJ exome AF: 0.718

Gnomad4 EAS exome AF: 0.533

Gnomad4 SAS exome AF: 0.647

Gnomad4 FIN exome AF: 0.761

Gnomad4 NFE exome AF: 0.770

Gnomad4 OTH exome AF: 0.742

GnomAD4 genome AF: 0.772 AC: 117124 AN: 151748 Hom.: 45598 Cov.: 35 AF XY: 0.769 AC XY: 57033 AN XY: 74136

Gnomad4 AFR AF: 0.837

Gnomad4 AMR AF: 0.760

Gnomad4 ASJ AF: 0.716

Gnomad4 EAS AF: 0.510

Gnomad4 SAS AF: 0.622

Gnomad4 FIN AF: 0.780

Gnomad4 NFE AF: 0.767

Gnomad4 OTH AF: 0.751

Alfa AF: 0.756 Hom.: 5341

Bravo AF: 0.777

Asia WGS AF: 0.598 AC: 2081 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.36
DANN	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3026750; hg19: chr10-43607756;