rs13230

Positions:

• chr21-39397364-A-G
• chr21-39397364-A-C
• chr21-39397364-A-T

Variant summary

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

The NM_004627.6(GET1):​c.*425A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.655 in 158,334 control chromosomes in the GnomAD database, including 34,477 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 0.65 (32999 hom., cov: 33)
  • Exomes 𝑓: 0.68 (1478 hom.)
• Consequence: GET1 NM_004627.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.84

Genes affected

GET1 (HGNC:12790): (guided entry of tail-anchored proteins factor 1) This gene is located in the candidate region for congenital heart disease (CHD) in Down syndrome (DS). It encodes a basic protein that functions as a receptor that promotes insertion of tail-anchored proteins in the endoplasmic reticulum membrane. This gene is located at a maternally-methylated differentially methylated region (DMR); however, its transcription may be biallelic, not imprinted. Alternative splicing results in different transcript variants. A pseudogene has been defined on chromosome 4. [provided by RefSeq, Apr 2017]

GET1-SH3BGR (HGNC:54635): (GET1-SH3BGR readthrough) This locus represents naturally occurring readthrough transcription between the neighboring WRB (tryptophan rich basic protein) and SH3BGR (SH3 domain binding glutamate-rich protein) genes on chromosome 21. Readthrough transcripts may encode fusion proteins that shares sequence identity with each individual gene product. [provided by RefSeq, Apr 2017]

GET1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.754 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GET1	NM_004627.6	c.*425A>G		3_prime_UTR_variant	5/5	ENST00000649170.1	NP_004618.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GET1	ENST00000649170.1	c.*425A>G		3_prime_UTR_variant	5/5		NM_004627.6	ENSP00000496813.1
GET1-SH3BGR	ENST00000647779.1	c.336+5528A>G		intron_variant				ENSP00000497977.1

Frequencies

GnomAD3 genomes AF: 0.654 AC: 99409 AN: 151986 Hom.: 32964 Cov.: 33

Gnomad AFR AF: 0.538

Gnomad AMI AF: 0.739

Gnomad AMR AF: 0.693

Gnomad ASJ AF: 0.655

Gnomad EAS AF: 0.775

Gnomad SAS AF: 0.711

Gnomad FIN AF: 0.779

Gnomad MID AF: 0.617

Gnomad NFE AF: 0.682

Gnomad OTH AF: 0.673

GnomAD4 exome AF: 0.685 AC: 4266 AN: 6230 Hom.: 1478 Cov.: 0 AF XY: 0.679 AC XY: 2177 AN XY: 3204

Gnomad4 AFR exome AF: 0.549

Gnomad4 AMR exome AF: 0.715

Gnomad4 ASJ exome AF: 0.677

Gnomad4 EAS exome AF: 0.807

Gnomad4 SAS exome AF: 0.679

Gnomad4 FIN exome AF: 0.763

Gnomad4 NFE exome AF: 0.678

Gnomad4 OTH exome AF: 0.675

GnomAD4 genome AF: 0.654 AC: 99496 AN: 152104 Hom.: 32999 Cov.: 33 AF XY: 0.662 AC XY: 49243 AN XY: 74354

Gnomad4 AFR AF: 0.539

Gnomad4 AMR AF: 0.694

Gnomad4 ASJ AF: 0.655

Gnomad4 EAS AF: 0.774

Gnomad4 SAS AF: 0.710

Gnomad4 FIN AF: 0.779

Gnomad4 NFE AF: 0.682

Gnomad4 OTH AF: 0.673

Alfa AF: 0.662 Hom.: 12529

Bravo AF: 0.645

Asia WGS AF: 0.750 AC: 2609 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	12
DANN	Benign	0.73

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: rs13230; hg19: chr21-40769290;