rs73467954

chr9-77318462-T-Cchr9-77318462-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_033305.3(VPS13A):c.5184T>C(p.Ser1728=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000685 in 1,613,886 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (2 hom.)
• Consequence: VPS13A NM_033305.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.171

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 9-77318462-T-C is Benign according to our data. Variant chr9-77318462-T-C is described in ClinVar as [Benign]. Clinvar id is 448866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-77318462-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.171 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00366 (557/152308) while in subpopulation AFR AF= 0.0128 (530/41566). AF 95% confidence interval is 0.0119. There are 3 homozygotes in gnomad4. There are 268 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13A	NM_033305.3	c.5184T>C	p.Ser1728=	synonymous_variant	41/72	ENST00000360280.8
VPS13A	NM_001018037.2	c.5067T>C	p.Ser1689=	synonymous_variant	40/71
VPS13A	NM_015186.4	c.5184T>C	p.Ser1728=	synonymous_variant	41/69
VPS13A	NM_001018038.3	c.5184T>C	p.Ser1728=	synonymous_variant	41/69

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13A	ENST00000360280.8	c.5184T>C	p.Ser1728=	synonymous_variant	41/72	1	NM_033305.3	P4

Frequencies

GnomAD3 genomes AF: 0.00365 AC: 555 AN: 152190 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0127

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

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: 0.0000294

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000903 AC: 226 AN: 250194 Hom.: 0 AF XY: 0.000651 AC XY: 88 AN XY: 135278

Gnomad AFR exome AF: 0.0121

Gnomad AMR exome AF: 0.000666

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000444

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000375 AC: 548 AN: 1461578 Hom.: 2 Cov.: 31 AF XY: 0.000337 AC XY: 245 AN XY: 727094

Gnomad4 AFR exome AF: 0.0122

Gnomad4 AMR exome AF: 0.000738

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000576

Gnomad4 OTH exome AF: 0.000662

GnomAD4 genome AF: 0.00366 AC: 557 AN: 152308 Hom.: 3 Cov.: 32 AF XY: 0.00360 AC XY: 268 AN XY: 74482

Gnomad4 AFR AF: 0.0128

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00248 Hom.: 1

Bravo AF: 0.00433

Asia WGS AF: 0.000577 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 29, 2017

- -

Chorea-acanthocytosis Benign:1

Likely benign, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 06, 2019

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	7.8
Dann	Benign	0.58

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

Publications

LitVar

Other links and lift over

dbSNP: rs73467954; hg19: chr9-79933378;