NM_004627.6:c.46A>G

Variant names:

• chr21-39380430-A-G
• NM_004627.6:c.46A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004627.6(GET1):​c.46A>G​(p.Ser16Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: GET1 NM_004627.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.22
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15141168).

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.46A>G	p.Ser16Gly	missense	Exon 1 of 5	NP_004618.2
	GET1-SH3BGR	NM_001317744.2		c.46A>G	p.Ser16Gly	missense	Exon 1 of 9	NP_001304673.1	A0A3B3ITX9
	GET1-SH3BGR	NM_001350300.2		c.46A>G	p.Ser16Gly	missense	Exon 1 of 7	NP_001337229.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GET1	ENST00000649170.1	MANE Select	c.46A>G	p.Ser16Gly	missense	Exon 1 of 5	ENSP00000496813.1	O00258-1
	GET1-SH3BGR	ENST00000647779.1		c.46A>G	p.Ser16Gly	missense	Exon 1 of 9	ENSP00000497977.1	A0A3B3ITX9
	GET1	ENST00000650376.1		c.-1+660A>G		intron	N/A	ENSP00000497103.1	O00258-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460692 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 726502

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26050

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 85864

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111564

Other (OTH) AF: 0.00 AC: 0 AN: 60312

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.092	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.22	N
PhyloP100		1.2
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.074
Sift	Benign	0.53	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.44
MutPred		0.58		Gain of loop (P = 0.024)
MVP		0.14
MPC		0.33
ClinPred		0.30	T
GERP RS		-0.23
PromoterAI		0.14	Neutral
Varity_R		0.28
gMVP		0.44
Mutation Taster		=90/10	polymorphism

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

hg19: chr21-40752356;