9-77316303-A-T

Position:

• chr9-77316303-A-T

Variant summary

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

The NM_033305.3(VPS13A):​c.4760A>T​(p.Tyr1587Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign 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. Y1587C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VPS13A NM_033305.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.71

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS13A	NM_033305.3	c.4760A>T	p.Tyr1587Phe	missense_variant	39/72	ENST00000360280.8	NP_150648.2
VPS13A	NM_001018037.2	c.4643A>T	p.Tyr1548Phe	missense_variant	38/71		NP_001018047.1
VPS13A	NM_015186.4	c.4760A>T	p.Tyr1587Phe	missense_variant	39/69		NP_056001.1
VPS13A	NM_001018038.3	c.4760A>T	p.Tyr1587Phe	missense_variant	39/69		NP_001018048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS13A	ENST00000360280.8	c.4760A>T	p.Tyr1587Phe	missense_variant	39/72	1	NM_033305.3	ENSP00000353422.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461216 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726890

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Uncertain	23
DANN	Benign	0.93
DEOGEN2	Benign	0.13	.;.;T;.;.;.;T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.78	.;T;.;.;T;T;T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.080	T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.1	L;.;L;L;L;L;L
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.22	N;N;N;N;.;.;.
REVEL	Benign	0.050
Sift	Benign	0.052	T;D;D;T;.;.;.
Sift4G	Benign	0.23	T;T;T;T;.;.;.
Polyphen		0.012	B;B;B;B;B;B;B
Vest4		0.26
MutPred		0.36		Gain of methylation at K1588 (P = 0.026);.;Gain of methylation at K1588 (P = 0.026);Gain of methylation at K1588 (P = 0.026);Gain of methylation at K1588 (P = 0.026);Gain of methylation at K1588 (P = 0.026);Gain of methylation at K1588 (P = 0.026);
MVP		0.095
MPC		0.13
ClinPred		0.14	T
GERP RS		1.2
Varity_R		0.054
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.55		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.55		Position offset: 6

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs149840356; hg19: chr9-79931219;