21-39380389-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.73

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:):

ACMG classification

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/exons	MANE	UniProt
GET1	NM_004627.6	c.5G>C	p.Ser2Thr	missense_variant	1/5	ENST00000649170.1
GET1-SH3BGR	NR_146618.2	n.64G>C		non_coding_transcript_exon_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GET1	ENST00000649170.1	c.5G>C	p.Ser2Thr	missense_variant	1/5		NM_004627.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000340 AC: 8 AN: 235328 Hom.: 0 AF XY: 0.0000391 AC XY: 5 AN XY: 127730

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: 7 AN: 1453066 Hom.: 0 Cov.: 30 AF XY: 0.00000692 AC XY: 5 AN XY: 722068

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.: 32

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2024

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	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	18
Dann	Benign	0.87
DEOGEN2	Benign	0.092	T;T;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.50	D
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.078	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.76	N;N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.56	T
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	T
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

Other links and lift over

dbSNP: rs752877318; hg19: chr21-40752315;