19-12748000-A-G

Variant names:

• chr19-12748000-A-G
• rs773820370
• NM_004317.4:c.943A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004317.4(GET3):​c.943A>G​(p.Ile315Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000412 in 1,457,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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: 0.0000041 (0 hom.)
• Consequence: GET3 NM_004317.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.23

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 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=0.14680642).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GET3	NM_004317.4	c.943A>G	p.Ile315Val	missense_variant	Exon 7 of 7	ENST00000357332.8	NP_004308.2
GET3	NM_001371488.1	c.943A>G	p.Ile315Val	missense_variant	Exon 8 of 8		NP_001358417.1
GET3	NM_001371489.1	c.943A>G	p.Ile315Val	missense_variant	Exon 8 of 8		NP_001358418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GET3	ENST00000357332.8	c.943A>G	p.Ile315Val	missense_variant	Exon 7 of 7	1	NM_004317.4	ENSP00000349887.3
GET3	ENST00000591090.5	c.943A>G	p.Ile315Val	missense_variant	Exon 8 of 8	5		ENSP00000466379.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000412 AC: 6 AN: 1457944 Hom.: 0 Cov.: 31 AF XY: 0.00000414 AC XY: 3 AN XY: 724830

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000451

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

May 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.943A>G (p.I315V) alteration is located in exon 7 (coding exon 7) of the ASNA1 gene. This alteration results from a A to G substitution at nucleotide position 943, causing the isoleucine (I) at amino acid position 315 to be replaced by a valine (V). 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	0.10
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	20
DANN	Benign	0.87
DEOGEN2	Benign	0.24	T;T;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.13
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;D;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.18	N;N;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.21	.;N;.
REVEL	Benign	0.20
Sift	Benign	1.0	.;T;.
Sift4G	Benign	0.75	T;T;T
Polyphen		0.025	B;B;.
Vest4		0.38
MutPred		0.53		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;
MVP		0.13
MPC		0.64
ClinPred		0.55	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.48

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: rs773820370; hg19: chr19-12858814;