Genetic Variant GET1:p.Ser2Thr (chr21-39380389-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004627.6(GET1):c.5G>C(p.Ser2Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000482 in 1,453,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.73

Variant links:

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 links:

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]

GET1-SH3BGR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.077973574).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GET1	NM_004627.6 link	c.5G>C	p.Ser2Thr	missense_variant	Exon 1 of 5	ENST00000649170.1	NP_004618.2	O00258-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GET1	ENST00000649170.1 link	c.5G>C	p.Ser2Thr	missense_variant	Exon 1 of 5		NM_004627.6	ENSP00000496813.1		O00258-1
GET1-SH3BGR	ENST00000647779.1 link	c.5G>C	p.Ser2Thr	missense_variant	Exon 1 of 9			ENSP00000497977.1		A0A3B3ITX9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000340

AC:

AN:

235328

Hom.:

AF XY:

0.0000391

AC XY:

AN XY:

127730

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000446

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000482

AC:

AN:

1453066

Hom.:

Cov.:

AF XY:

0.00000692

AC XY:

AN XY:

722068

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000177

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5G>C (p.S2T) alteration is located in exon 1 (coding exon 1) of the WRB gene. This alteration results from a G to C substitution at nucleotide position 5, causing the serine (S) at amino acid position 2 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.092

T;T;.

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.40

.;T;T

M_CAP

Benign

0.0041

MetaRNN

Benign

0.078

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.76

N;N;.

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.78

N;.;.

REVEL

Benign

0.044

Sift

Benign

0.46

T;.;.

Sift4G

Benign

0.66

T;.;.

Polyphen

0.0

B;B;.

Vest4

0.19

MutPred

0.16

Gain of catalytic residue at S2 (P = 0.0669);Gain of catalytic residue at S2 (P = 0.0669);Gain of catalytic residue at S2 (P = 0.0669);

MVP

0.067

MPC

0.33

ClinPred

0.055

GERP RS

3.0

Varity_R

0.10

gMVP

0.53

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over