chr9-77356719-A-G

Position:

• chr9-77356719-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033305.3(VPS13A):​c.7658A>G​(p.Asp2553Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: VPS13A NM_033305.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.69

Genes affected

VPS13A (HGNC:1908): (vacuolar protein sorting 13 homolog A) The protein encoded by this gene may control steps in the cycling of proteins through the trans-Golgi network to endosomes, lysosomes and the plasma membrane. Mutations in this gene cause the autosomal recessive disorder, chorea-acanthocytosis. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19173756).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS13A	NM_033305.3	c.7658A>G	p.Asp2553Gly	missense_variant	55/72	ENST00000360280.8	NP_150648.2
VPS13A	NM_001018037.2	c.7541A>G	p.Asp2514Gly	missense_variant	54/71		NP_001018047.1
VPS13A	NM_015186.4	c.7658A>G	p.Asp2553Gly	missense_variant	55/69		NP_056001.1
VPS13A	NM_001018038.3	c.7658A>G	p.Asp2553Gly	missense_variant	55/69		NP_001018048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS13A	ENST00000360280.8	c.7658A>G	p.Asp2553Gly	missense_variant	55/72	1	NM_033305.3	ENSP00000353422.3
VPS13A	ENST00000376636.7	c.7541A>G	p.Asp2514Gly	missense_variant	54/71	1		ENSP00000365823.3
VPS13A	ENST00000643348.1	c.7658A>G	p.Asp2553Gly	missense_variant	55/69			ENSP00000493592.1
VPS13A	ENST00000645632.1	c.7658A>G	p.Asp2553Gly	missense_variant	55/69			ENSP00000496361.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 32

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

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152210 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74366

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	26
DANN	Benign	0.29
DEOGEN2	Benign	0.11	.;.;T;.;.;.;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	.;T;.;.;T;T;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.19	T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.66	N;.;N;N;N;N;N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.53	N;N;N;N;.;.;.
REVEL	Benign	0.15
Sift	Benign	1.0	T;T;T;T;.;.;.
Sift4G	Benign	0.67	T;T;T;T;.;.;.
Polyphen		0.91	P;B;D;P;P;P;D
Vest4		0.56
MutPred		0.54		Gain of glycosylation at S2552 (P = 0.0449);.;Gain of glycosylation at S2552 (P = 0.0449);Gain of glycosylation at S2552 (P = 0.0449);Gain of glycosylation at S2552 (P = 0.0449);Gain of glycosylation at S2552 (P = 0.0449);Gain of glycosylation at S2552 (P = 0.0449);
MVP		0.70
MPC		0.68
ClinPred		0.97	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs758912053; hg19: chr9-79971635; COSMIC: COSV62428739; COSMIC: COSV62428739;