NM_004317.4:c.943A>G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 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. 14/22 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: 0.0000041 (0 hom.)
• Consequence: GET3 NM_004317.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.23
• Publications: 0 publications found

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]

GET3 Gene-Disease associations (from GenCC):

• dilated cardiomyopathy

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.2073 (below the threshold of 3.09). Trascript score misZ: 2.1824 (below the threshold of 3.09).
• BP4: Computational evidence support a benign effect (MetaRNN=0.14680642).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004317.4. 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
	GET3	NM_004317.4	MANE Select	c.943A>G	p.Ile315Val	missense	Exon 7 of 7	NP_004308.2	O43681
	GET3	NM_001371488.1		c.943A>G	p.Ile315Val	missense	Exon 8 of 8	NP_001358417.1	O43681
	GET3	NM_001371489.1		c.943A>G	p.Ile315Val	missense	Exon 8 of 8	NP_001358418.1	O43681

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GET3	ENST00000357332.8	TSL:1 MANE Select	c.943A>G	p.Ile315Val	missense	Exon 7 of 7	ENSP00000349887.3	O43681
	GET3	ENST00000935719.1		c.1084A>G	p.Ile362Val	missense	Exon 8 of 8	ENSP00000605778.1
	GET3	ENST00000591090.5	TSL:5	c.943A>G	p.Ile315Val	missense	Exon 8 of 8	ENSP00000466379.1	O43681

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

African (AFR) AF: 0.00 AC: 0 AN: 33430

American (AMR) AF: 0.00 AC: 0 AN: 44500

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25952

East Asian (EAS) AF: 0.00 AC: 0 AN: 39594

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53322

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00000451 AC: 5 AN: 1109288

Other (OTH) AF: 0.00 AC: 0 AN: 60248

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

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	0.10
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	20
DANN	Benign	0.87
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.13
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.18	N
PhyloP100		8.2
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.21	N
REVEL	Benign	0.20
Sift	Benign	1.0	T
Sift4G	Benign	0.75	T
Polyphen		0.025	B
Vest4		0.38
MutPred		0.53		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
Mutation Taster		=80/20	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

dbSNP: rs773820370; hg19: chr19-12858814;