21-39391828-G-A

Variant names:

• chr21-39391828-G-A
• rs35946782
• NM_004627.6:c.328G>A

Variant summary

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

The NM_004627.6(GET1):​c.328G>A​(p.Val110Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00309 in 1,614,044 control chromosomes in the GnomAD database, including 137 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V110L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.017 (72 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (65 hom.)
• Consequence: GET1 NM_004627.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.601
• Publications: 6 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 (MetaRNN=0.0017336905).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0568 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.328G>A	p.Val110Ile	missense	Exon 3 of 5	NP_004618.2
	GET1-SH3BGR	NM_001317744.2		c.328G>A	p.Val110Ile	missense	Exon 3 of 9	NP_001304673.1	A0A3B3ITX9
	GET1-SH3BGR	NM_001350300.2		c.328G>A	p.Val110Ile	missense	Exon 3 of 7	NP_001337229.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GET1	ENST00000649170.1	MANE Select	c.328G>A	p.Val110Ile	missense	Exon 3 of 5	ENSP00000496813.1	O00258-1
	GET1-SH3BGR	ENST00000647779.1		c.328G>A	p.Val110Ile	missense	Exon 3 of 9	ENSP00000497977.1	A0A3B3ITX9
	GET1	ENST00000380708.5	TSL:1	c.226G>A	p.Val76Ile	missense	Exon 3 of 5	ENSP00000370084.1	O00258-2

Frequencies

GnomAD3 genomes AF: 0.0167 AC: 2542 AN: 152126 Hom.: 71 Cov.: 33

Gnomad AFR AF: 0.0587

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00909

GnomAD2 exomes AF: 0.00425 AC: 1068 AN: 251452 AF XY: 0.00293

Gnomad AFR exome AF: 0.0595

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000246

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.00167 AC: 2437 AN: 1461800 Hom.: 65 Cov.: 30 AF XY: 0.00142 AC XY: 1033 AN XY: 727214

African (AFR) AF: 0.0584 AC: 1953 AN: 33462

American (AMR) AF: 0.00244 AC: 109 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00416 AC: 24 AN: 5766

European-Non Finnish (NFE) AF: 0.000120 AC: 133 AN: 1111970

Other (OTH) AF: 0.00354 AC: 214 AN: 60390

GnomAD4 genome AF: 0.0168 AC: 2553 AN: 152244 Hom.: 72 Cov.: 33 AF XY: 0.0162 AC XY: 1204 AN XY: 74448

African (AFR) AF: 0.0587 AC: 2440 AN: 41536

American (AMR) AF: 0.00477 AC: 73 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68022

Other (OTH) AF: 0.00900 AC: 19 AN: 2112

Alfa AF: 0.00602 Hom.: 51

Bravo AF: 0.0187

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0583 AC: 257

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00555 AC: 674

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000356

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.058
DANN	Benign	0.56
DEOGEN2	Benign	0.050	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.4	N
PhyloP100		0.60
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.091
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.14
MVP		0.030
MPC		0.30
ClinPred		0.0029	T
GERP RS		-8.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.047
gMVP		0.34
Mutation Taster		=99/1	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: rs35946782; hg19: chr21-40763754;