21-39397091-G-T

Variant names:

• chr21-39397091-G-T
• rs1060180
• ENST00000466787.1:n.*978G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000466787.1(GET1):​n.*978G>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.679 in 764,006 control chromosomes in the GnomAD database, including 178,322 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 (32628 hom., cov: 31)
  • Exomes 𝑓: 0.69 (145694 hom.)
• Consequence: GET1 ENST00000466787.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.904
• Publications: 17 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.756 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GET1	NM_004627.6	c.*152G>T		3_prime_UTR_variant	Exon 5 of 5	ENST00000649170.1	NP_004618.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GET1	ENST00000649170.1	c.*152G>T		3_prime_UTR_variant	Exon 5 of 5		NM_004627.6	ENSP00000496813.1
GET1-SH3BGR	ENST00000647779.1	c.336+5255G>T		intron_variant	Intron 3 of 8			ENSP00000497977.1

Frequencies

GnomAD3 genomes AF: 0.650 AC: 98678 AN: 151814 Hom.: 32602 Cov.: 31

Gnomad AFR AF: 0.524

Gnomad AMI AF: 0.739

Gnomad AMR AF: 0.692

Gnomad ASJ AF: 0.654

Gnomad EAS AF: 0.776

Gnomad SAS AF: 0.710

Gnomad FIN AF: 0.779

Gnomad MID AF: 0.621

Gnomad NFE AF: 0.681

Gnomad OTH AF: 0.668

GnomAD4 exome AF: 0.686 AC: 420032 AN: 612074 Hom.: 145694 Cov.: 8 AF XY: 0.688 AC XY: 218829 AN XY: 318152

African (AFR) AF: 0.528 AC: 8005 AN: 15164

American (AMR) AF: 0.713 AC: 14063 AN: 19736

Ashkenazi Jewish (ASJ) AF: 0.659 AC: 9860 AN: 14966

East Asian (EAS) AF: 0.802 AC: 25698 AN: 32034

South Asian (SAS) AF: 0.707 AC: 34471 AN: 48768

European-Finnish (FIN) AF: 0.776 AC: 25616 AN: 33006

Middle Eastern (MID) AF: 0.603 AC: 1753 AN: 2908

European-Non Finnish (NFE) AF: 0.675 AC: 279752 AN: 414368

Other (OTH) AF: 0.669 AC: 20814 AN: 31124

GnomAD4 genome AF: 0.650 AC: 98751 AN: 151932 Hom.: 32628 Cov.: 31 AF XY: 0.659 AC XY: 48924 AN XY: 74282

African (AFR) AF: 0.524 AC: 21697 AN: 41388

American (AMR) AF: 0.692 AC: 10566 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.654 AC: 2272 AN: 3472

East Asian (EAS) AF: 0.776 AC: 4009 AN: 5168

South Asian (SAS) AF: 0.710 AC: 3419 AN: 4816

European-Finnish (FIN) AF: 0.779 AC: 8229 AN: 10562

Middle Eastern (MID) AF: 0.610 AC: 178 AN: 292

European-Non Finnish (NFE) AF: 0.681 AC: 46294 AN: 67948

Other (OTH) AF: 0.668 AC: 1413 AN: 2114

Alfa AF: 0.660 Hom.: 13856

Bravo AF: 0.640

Asia WGS AF: 0.746 AC: 2593 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.4
DANN	Benign	0.61
PhyloP100		0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1060180; hg19: chr21-40769017;