rs2837005

Variant names:

• chr21-39397881-T-C
• rs2837005
• NM_004627.6:c.*942T>C

Variant summary

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

The ENST00000649170.1(GET1):​c.*942T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.668 in 152,110 control chromosomes in the GnomAD database, including 34,213 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 0.67 (34213 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: GET1 ENST00000649170.1 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.530
• 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.755 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000649170.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GET1	NM_004627.6	MANE Select	c.*942T>C		3_prime_UTR	Exon 5 of 5	NP_004618.2
	GET1	NR_146614.2		n.2139T>C		non_coding_transcript_exon	Exon 5 of 5
	GET1	NR_146616.2		n.2053T>C		non_coding_transcript_exon	Exon 5 of 5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GET1	ENST00000649170.1	MANE Select	c.*942T>C		3_prime_UTR	Exon 5 of 5	ENSP00000496813.1
	GET1	ENST00000380708.5	TSL:1	c.*942T>C		3_prime_UTR	Exon 5 of 5	ENSP00000370084.1
	GET1-SH3BGR	ENST00000647779.1		c.336+6045T>C		intron	N/A	ENSP00000497977.1

Frequencies

GnomAD3 genomes AF: 0.668 AC: 101584 AN: 151992 Hom.: 34171 Cov.: 33

Gnomad AFR AF: 0.589

Gnomad AMI AF: 0.739

Gnomad AMR AF: 0.697

Gnomad ASJ AF: 0.654

Gnomad EAS AF: 0.775

Gnomad SAS AF: 0.711

Gnomad FIN AF: 0.779

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.682

Gnomad OTH AF: 0.681

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.668 AC: 101679 AN: 152110 Hom.: 34213 Cov.: 33 AF XY: 0.676 AC XY: 50292 AN XY: 74370

African (AFR) AF: 0.589 AC: 24435 AN: 41472

American (AMR) AF: 0.698 AC: 10659 AN: 15276

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

East Asian (EAS) AF: 0.775 AC: 4013 AN: 5180

South Asian (SAS) AF: 0.711 AC: 3422 AN: 4816

European-Finnish (FIN) AF: 0.779 AC: 8236 AN: 10578

Middle Eastern (MID) AF: 0.609 AC: 179 AN: 294

European-Non Finnish (NFE) AF: 0.682 AC: 46349 AN: 67996

Other (OTH) AF: 0.681 AC: 1440 AN: 2114

Alfa AF: 0.674 Hom.: 11959

Bravo AF: 0.660

Asia WGS AF: 0.755 AC: 2627 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	6.3
DANN	Benign	0.63
PhyloP100		-0.53
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: rs2837005; hg19: chr21-40769807;