19-12745402-C-T

Variant names:

• chr19-12745402-C-T
• rs144446697
• NM_004317.4:c.335C>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.335C>T​(p.Ala112Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,611,460 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A112G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GET3 NM_004317.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.23
• Publications: 1 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=0.3478698).

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.335C>T	p.Ala112Val	missense	Exon 3 of 7	NP_004308.2	O43681
	GET3	NM_001371488.1		c.335C>T	p.Ala112Val	missense	Exon 4 of 8	NP_001358417.1	O43681
	GET3	NM_001371489.1		c.335C>T	p.Ala112Val	missense	Exon 4 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.335C>T	p.Ala112Val	missense	Exon 3 of 7	ENSP00000349887.3	O43681
	GET3	ENST00000935719.1		c.476C>T	p.Ala159Val	missense	Exon 4 of 8	ENSP00000605778.1
	GET3	ENST00000591090.5	TSL:5	c.335C>T	p.Ala112Val	missense	Exon 4 of 8	ENSP00000466379.1	O43681

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152082 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 249154 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459378 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726012

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50996

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111966

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152082 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74290

African (AFR) AF: 0.00 AC: 0 AN: 41392

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.00 AC: 0 AN: 2086

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	0.20
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.60	N
PhyloP100		7.2
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.15
Sift	Benign	0.26	T
Sift4G	Benign	0.23	T
Polyphen		0.0080	B
Vest4		0.81
MutPred		0.43		Loss of disorder (P = 0.0935)
MVP		0.41
MPC		0.72
ClinPred		0.74	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.91
Mutation Taster		=26/74	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: rs144446697; hg19: chr19-12856216;