19-12737528-G-C

Variant names:

• chr19-12737528-G-C
• rs138730527
• NM_004317.4:c.23G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004317.4(GET3):​c.23G>C​(p.Trp8Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000124 in 1,570,532 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: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: GET3 NM_004317.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.09

Genes affected

GET3 (HGNC:752): (guided entry of tail-anchored proteins factor 3, ATPase) This gene represents the human homolog of the bacterial arsA gene, encoding the arsenite-stimulated ATPase component of the arsenite transporter responsible for resistance to arsenicals. This protein is also a central component of a transmembrane domain (TMD) recognition complex (TRC) that is involved in the post-translational delivery of tail-anchored (TA) proteins from the cytosol to the endoplasmic reticulum (ER). It recognizes and selectively binds the TMD of TA proteins in the cytosol, and delivers them to the ER for insertion. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.052227944).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GET3	NM_004317.4	c.23G>C	p.Trp8Ser	missense_variant	Exon 1 of 7	ENST00000357332.8	NP_004308.2
GET3	NM_001371488.1	c.23G>C	p.Trp8Ser	missense_variant	Exon 2 of 8		NP_001358417.1
GET3	NM_001371489.1	c.23G>C	p.Trp8Ser	missense_variant	Exon 2 of 8		NP_001358418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GET3	ENST00000357332.8	c.23G>C	p.Trp8Ser	missense_variant	Exon 1 of 7	1	NM_004317.4	ENSP00000349887.3
GET3	ENST00000591090.5	c.23G>C	p.Trp8Ser	missense_variant	Exon 2 of 8	5		ENSP00000466379.1
GET3	ENST00000590633.1	n.32G>C		non_coding_transcript_exon_variant	Exon 1 of 3	2

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000174 AC: 35 AN: 200656 Hom.: 0 AF XY: 0.000164 AC XY: 18 AN XY: 110070

Gnomad AFR exome AF: 0.000324

Gnomad AMR exome AF: 0.000361

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000730

Gnomad SAS exome AF: 0.000236

Gnomad FIN exome AF: 0.0000552

Gnomad NFE exome AF: 0.000129

Gnomad OTH exome AF: 0.000414

GnomAD4 exome AF: 0.000124 AC: 176 AN: 1418224 Hom.: 0 Cov.: 30 AF XY: 0.000124 AC XY: 87 AN XY: 702654

Gnomad4 AFR exome AF: 0.000283

Gnomad4 AMR exome AF: 0.000326

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000818

Gnomad4 SAS exome AF: 0.000409

Gnomad4 FIN exome AF: 0.000215

Gnomad4 NFE exome AF: 0.0000888

Gnomad4 OTH exome AF: 0.000171

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74476

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000270 Hom.: 0

Bravo AF: 0.000151

ExAC AF: 0.000165 AC: 20

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 30, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.23G>C (p.W8S) alteration is located in exon 1 (coding exon 1) of the ASNA1 gene. This alteration results from a G to C substitution at nucleotide position 23, causing the tryptophan (W) at amino acid position 8 to be replaced by a serine (S). 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	0.14
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.28	T;.;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.052
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.51	.;T;T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.052	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;.;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	0.18	.;.;N
REVEL	Benign	0.12
Sift	Benign	0.22	.;.;T
Sift4G	Uncertain	0.020	D;T;D
Polyphen		0.020	B;.;B
Vest4		0.38
MVP		0.25
MPC		1.1
ClinPred		0.054	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.099
gMVP		0.84

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: rs138730527; hg19: chr19-12848342;