rs552113529

chr9-77344173-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The NM_033305.3(VPS13A):c.7047G>A(p.Glu2349=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000292 in 1,607,686 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: VPS13A NM_033305.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.31

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 9-77344173-G-A is Benign according to our data. Variant chr9-77344173-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 586933.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=1.31 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13A	NM_033305.3	c.7047G>A	p.Glu2349=	synonymous_variant	51/72	ENST00000360280.8
VPS13A	NM_001018037.2	c.6930G>A	p.Glu2310=	synonymous_variant	50/71
VPS13A	NM_015186.4	c.7047G>A	p.Glu2349=	synonymous_variant	51/69
VPS13A	NM_001018038.3	c.7047G>A	p.Glu2349=	synonymous_variant	51/69

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13A	ENST00000360280.8	c.7047G>A	p.Glu2349=	synonymous_variant	51/72	1	NM_033305.3	P4
VPS13A	ENST00000376636.7	c.6930G>A	p.Glu2310=	synonymous_variant	50/71	1
VPS13A	ENST00000643348.1	c.7047G>A	p.Glu2349=	synonymous_variant	51/69
VPS13A	ENST00000645632.1	c.7047G>A	p.Glu2349=	synonymous_variant	51/69			A1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152022 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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

GnomAD3 exomes AF: 0.0000597 AC: 15 AN: 251308 Hom.: 0 AF XY: 0.0000442 AC XY: 6 AN XY: 135868

Gnomad AFR exome AF: 0.000679

Gnomad AMR exome AF: 0.000116

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000172 AC: 25 AN: 1455546 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 724528

Gnomad4 AFR exome AF: 0.000510

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000665

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74380

Gnomad4 AFR AF: 0.000506

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

Alfa AF: 0.000135 Hom.: 0

Bravo AF: 0.000208

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 10, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 20, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	11
Dann	Benign	0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: 12

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

Publications

LitVar

Other links and lift over

dbSNP: rs552113529; hg19: chr9-79959089;