rs999134544

Variant names:

• chr19-12737608-C-T
• rs999134544
• NM_004317.4:c.103C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_004317.4(GET3):​c.103C>T​(p.Arg35Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: GET3 NM_004317.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.05
• 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 2 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=0.30848262).

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.103C>T	p.Arg35Cys	missense	Exon 1 of 7	NP_004308.2	O43681
	GET3	NM_001371488.1		c.103C>T	p.Arg35Cys	missense	Exon 2 of 8	NP_001358417.1	O43681
	GET3	NM_001371489.1		c.103C>T	p.Arg35Cys	missense	Exon 2 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.103C>T	p.Arg35Cys	missense	Exon 1 of 7	ENSP00000349887.3	O43681
	GET3	ENST00000935719.1		c.103C>T	p.Arg35Cys	missense	Exon 1 of 8	ENSP00000605778.1
	GET3	ENST00000591090.5	TSL:5	c.103C>T	p.Arg35Cys	missense	Exon 2 of 8	ENSP00000466379.1	O43681

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459282 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725978

African (AFR) AF: 0.00 AC: 0 AN: 33330

American (AMR) AF: 0.00 AC: 0 AN: 44332

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26056

East Asian (EAS) AF: 0.00 AC: 0 AN: 39374

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85874

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53182

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111134

Other (OTH) AF: 0.00 AC: 0 AN: 60294

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

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	0.25
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Benign	-0.082
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		5.1
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.17
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.014	D
Polyphen		0.016	B
Vest4		0.55
MutPred		0.47		Loss of solvent accessibility (P = 0.0079)
MVP		0.32
MPC		0.94
ClinPred		0.99	D
GERP RS		4.5
PromoterAI		-0.052	Neutral
Varity_R		0.43
gMVP		0.57
Mutation Taster		=56/44	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: rs999134544; hg19: chr19-12848422;