chr21-39397364-A-G

Variant names:

• chr21-39397364-A-G
• rs13230
• NM_004627.6:c.*425A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 13 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=-0.65).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.754 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004627.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GET1	NM_004627.6	MANE Select	c.*425A>G		3_prime_UTR	Exon 5 of 5	NP_004618.2
	GET1	NM_001350293.1		c.*425A>G		3_prime_UTR	Exon 5 of 5	NP_001337222.1
	GET1	NM_001146218.3		c.*425A>G		3_prime_UTR	Exon 5 of 5	NP_001139690.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GET1	ENST00000649170.1	MANE Select	c.*425A>G		3_prime_UTR	Exon 5 of 5	ENSP00000496813.1
	GET1	ENST00000380708.5	TSL:1	c.*425A>G		3_prime_UTR	Exon 5 of 5	ENSP00000370084.1
	GET1-SH3BGR	ENST00000647779.1		c.336+5528A>G		intron	N/A	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

African (AFR) AF: 0.549 AC: 56 AN: 102

American (AMR) AF: 0.715 AC: 379 AN: 530

Ashkenazi Jewish (ASJ) AF: 0.677 AC: 107 AN: 158

East Asian (EAS) AF: 0.807 AC: 121 AN: 150

South Asian (SAS) AF: 0.679 AC: 349 AN: 514

European-Finnish (FIN) AF: 0.763 AC: 151 AN: 198

Middle Eastern (MID) AF: 0.583 AC: 7 AN: 12

European-Non Finnish (NFE) AF: 0.678 AC: 2857 AN: 4212

Other (OTH) AF: 0.675 AC: 239 AN: 354

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

African (AFR) AF: 0.539 AC: 22348 AN: 41496

American (AMR) AF: 0.694 AC: 10586 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.655 AC: 2272 AN: 3468

East Asian (EAS) AF: 0.774 AC: 4010 AN: 5178

South Asian (SAS) AF: 0.710 AC: 3424 AN: 4820

European-Finnish (FIN) AF: 0.779 AC: 8236 AN: 10568

Middle Eastern (MID) AF: 0.605 AC: 178 AN: 294

European-Non Finnish (NFE) AF: 0.682 AC: 46346 AN: 67990

Other (OTH) AF: 0.673 AC: 1422 AN: 2114

Alfa AF: 0.662 Hom.: 15276

Bravo AF: 0.645

Asia WGS AF: 0.750 AC: 2609 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	12
DANN	Benign	0.73
PhyloP100		1.8
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: rs13230; hg19: chr21-40769290;