19-12738629-G-T

Variant names:

• chr19-12738629-G-T
• rs1802253
• NM_004317.4:c.280G>T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_004317.4(GET3):​c.280G>T​(p.Val94Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V94I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GET3 NM_004317.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.38
• 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 5 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). GenCC associations: The gene is linked to dilated cardiomyopathy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873

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.280G>T	p.Val94Phe	missense	Exon 2 of 7	NP_004308.2	O43681
	GET3	NM_001371488.1		c.280G>T	p.Val94Phe	missense	Exon 3 of 8	NP_001358417.1	O43681
	GET3	NM_001371489.1		c.280G>T	p.Val94Phe	missense	Exon 3 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.280G>T	p.Val94Phe	missense	Exon 2 of 7	ENSP00000349887.3	O43681
	GET3	ENST00000935719.1		c.280G>T	p.Val94Phe	missense	Exon 2 of 8	ENSP00000605778.1
	GET3	ENST00000591090.5	TSL:5	c.280G>T	p.Val94Phe	missense	Exon 3 of 8	ENSP00000466379.1	O43681

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		9.4
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.70		Gain of methylation at K93 (P = 0.0952)
MVP		0.77
MPC		2.0
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.99
gMVP		1.0
Mutation Taster		=4/96	disease causing

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: rs1802253; hg19: chr19-12849443;