rs73466090

Positions:

• chr9-77276145-A-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.2748A>G​(p.Glu916Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000544 in 1,613,190 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 0.0030 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (4 hom.)
• Consequence: VPS13A NM_033305.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.637

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=-0.83).
• BP6: Variant 9-77276145-A-G is Benign according to our data. Variant chr9-77276145-A-G is described in ClinVar as [Benign]. Clinvar id is 448859.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.637 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00301 (458/152284) while in subpopulation AFR AF= 0.0105 (437/41552). AF 95% confidence interval is 0.0097. There are 1 homozygotes in gnomad4. There are 231 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS13A	NM_033305.3	c.2748A>G	p.Glu916Glu	synonymous_variant	26/72	ENST00000360280.8	NP_150648.2
VPS13A	NM_001018037.2	c.2748A>G	p.Glu916Glu	synonymous_variant	26/71		NP_001018047.1
VPS13A	NM_015186.4	c.2748A>G	p.Glu916Glu	synonymous_variant	26/69		NP_056001.1
VPS13A	NM_001018038.3	c.2748A>G	p.Glu916Glu	synonymous_variant	26/69		NP_001018048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS13A	ENST00000360280.8	c.2748A>G	p.Glu916Glu	synonymous_variant	26/72	1	NM_033305.3	ENSP00000353422.3
VPS13A	ENST00000376636.7	c.2748A>G	p.Glu916Glu	synonymous_variant	26/71	1		ENSP00000365823.3
VPS13A	ENST00000643348.1	c.2748A>G	p.Glu916Glu	synonymous_variant	26/69			ENSP00000493592.1
VPS13A	ENST00000645632.1	c.2748A>G	p.Glu916Glu	synonymous_variant	26/69			ENSP00000496361.1

Frequencies

GnomAD3 genomes AF: 0.00300 AC: 457 AN: 152166 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

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: 0.0000147

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000705 AC: 177 AN: 251204 Hom.: 0 AF XY: 0.000515 AC XY: 70 AN XY: 135798

Gnomad AFR exome AF: 0.00941

Gnomad AMR exome AF: 0.000521

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: 0.0000352

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000287 AC: 419 AN: 1460906 Hom.: 4 Cov.: 31 AF XY: 0.000253 AC XY: 184 AN XY: 726768

Gnomad4 AFR exome AF: 0.0100

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.000613

GnomAD4 genome AF: 0.00301 AC: 458 AN: 152284 Hom.: 1 Cov.: 32 AF XY: 0.00310 AC XY: 231 AN XY: 74464

Gnomad4 AFR AF: 0.0105

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00239 Hom.: 1

Bravo AF: 0.00362

Asia WGS AF: 0.000578 AC: 3 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Mar 29, 2017

- -

Chorea-acanthocytosis Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.1
DANN	Benign	0.42

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: rs73466090; hg19: chr9-79891061;