19-12738573-C-G

Variant names:

• chr19-12738573-C-G
• rs864622036
• NM_004317.4:c.224C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004317.4(GET3):​c.224C>G​(p.Pro75Arg) 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. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GET3 NM_004317.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 7.40

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GET3	NM_004317.4	c.224C>G	p.Pro75Arg	missense_variant	Exon 2 of 7	ENST00000357332.8	NP_004308.2
GET3	NM_001371488.1	c.224C>G	p.Pro75Arg	missense_variant	Exon 3 of 8		NP_001358417.1
GET3	NM_001371489.1	c.224C>G	p.Pro75Arg	missense_variant	Exon 3 of 8		NP_001358418.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GET3	ENST00000357332.8	c.224C>G	p.Pro75Arg	missense_variant	Exon 2 of 7	1	NM_004317.4	ENSP00000349887.3
GET3	ENST00000591090.5	c.224C>G	p.Pro75Arg	missense_variant	Exon 3 of 8	5		ENSP00000466379.1
GET3	ENST00000590633.1	n.233C>G		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Prostate cancer Uncertain:1

-

Prostate Cancer Research Center, Institute of Biosciences and Medical Technology, University of Tampere

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;.;D;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	.;D;D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	3.4	M;.;M;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-8.8	.;.;D;.
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	.;.;D;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.98
MutPred		0.97		Gain of catalytic residue at P75 (P = 0.0344);Gain of catalytic residue at P75 (P = 0.0344);Gain of catalytic residue at P75 (P = 0.0344);.;
MVP		0.87
MPC		1.8
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.95
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs864622036; hg19: chr19-12849387; COSMIC: COSV54406586; COSMIC: COSV54406586;