9-77316303-A-G

Position:

• chr9-77316303-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_033305.3(VPS13A):​c.4760A>G​(p.Tyr1587Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00828 in 1,613,384 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y1587H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0053 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0086 (70 hom.)
• Consequence: VPS13A NM_033305.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• 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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0065418184).
• BP6: Variant 9-77316303-A-G is Benign according to our data. Variant chr9-77316303-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 448864.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, Uncertain_significance=1}. Variant chr9-77316303-A-G is described in Lovd as [Likely_benign]. Variant chr9-77316303-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00527 (802/152172) while in subpopulation NFE AF= 0.00949 (645/67936). AF 95% confidence interval is 0.00889. There are 3 homozygotes in gnomad4. There are 360 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS13A	NM_033305.3	c.4760A>G	p.Tyr1587Cys	missense_variant	39/72	ENST00000360280.8
VPS13A	NM_001018037.2	c.4643A>G	p.Tyr1548Cys	missense_variant	38/71
VPS13A	NM_015186.4	c.4760A>G	p.Tyr1587Cys	missense_variant	39/69
VPS13A	NM_001018038.3	c.4760A>G	p.Tyr1587Cys	missense_variant	39/69

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS13A	ENST00000360280.8	c.4760A>G	p.Tyr1587Cys	missense_variant	39/72	1	NM_033305.3	P4

Frequencies

GnomAD3 genomes AF: 0.00527 AC: 802 AN: 152054 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00949

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00457 AC: 1149 AN: 251150 Hom.: 1 AF XY: 0.00476 AC XY: 646 AN XY: 135726

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00487

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00327

Gnomad FIN exome AF: 0.00171

Gnomad NFE exome AF: 0.00766

Gnomad OTH exome AF: 0.00474

GnomAD4 exome AF: 0.00860 AC: 12564 AN: 1461212 Hom.: 70 Cov.: 30 AF XY: 0.00833 AC XY: 6053 AN XY: 726888

Gnomad4 AFR exome AF: 0.00129

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00640

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00380

Gnomad4 FIN exome AF: 0.00200

Gnomad4 NFE exome AF: 0.0103

Gnomad4 OTH exome AF: 0.00684

GnomAD4 genome AF: 0.00527 AC: 802 AN: 152172 Hom.: 3 Cov.: 32 AF XY: 0.00484 AC XY: 360 AN XY: 74402

Gnomad4 AFR AF: 0.00164

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00415

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.00949

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00699 Hom.: 6

Bravo AF: 0.00480

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.00791 AC: 68

ExAC AF: 0.00436 AC: 529

Asia WGS AF: 0.000867 AC: 3 AN: 3476

EpiCase AF: 0.00786

EpiControl AF: 0.00806

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 14, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	VPS13A: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Chorea-acanthocytosis Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 16, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	17
DANN	Benign	0.88
DEOGEN2	Benign	0.28	.;.;T;.;.;.;T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.79	.;T;.;.;T;T;T
MetaRNN	Benign	0.0065	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.51	N;.;N;N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.99	N;N;N;N;.;.;.
REVEL	Benign	0.069
Sift	Benign	0.13	T;T;T;T;.;.;.
Sift4G	Benign	0.093	T;T;T;T;.;.;.
Polyphen		0.0	B;B;B;B;B;B;B
Vest4		0.29
MVP		0.40
MPC		0.16
ClinPred		0.0045	T
GERP RS		1.2
Varity_R		0.064
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs149840356; hg19: chr9-79931219;