9-77318570-G-T

Variant names:

• chr9-77318570-G-T
• rs141528779
• NM_033305.3:c.5292G>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_033305.3(VPS13A):​c.5292G>T​(p.Leu1764Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.001 in 1,613,664 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L1764L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (3 hom.)
• Consequence: VPS13A NM_033305.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -2.23
• Publications: 1 publications found

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]

VPS13A Gene-Disease associations (from GenCC):

• chorea-acanthocytosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.022).
• BP6: Variant 9-77318570-G-T is Benign according to our data. Variant chr9-77318570-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 367388.
• BP7: Synonymous conserved (PhyloP=-2.22 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033305.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13A	NM_033305.3	MANE Select	c.5292G>T	p.Leu1764Leu	synonymous	Exon 41 of 72	NP_150648.2	Q96RL7-1
	VPS13A	NM_001018037.2		c.5175G>T	p.Leu1725Leu	synonymous	Exon 40 of 71	NP_001018047.1	Q96RL7-3
	VPS13A	NM_015186.4		c.5292G>T	p.Leu1764Leu	synonymous	Exon 41 of 69	NP_056001.1	Q96RL7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13A	ENST00000360280.8	TSL:1 MANE Select	c.5292G>T	p.Leu1764Leu	synonymous	Exon 41 of 72	ENSP00000353422.3	Q96RL7-1
	VPS13A	ENST00000376636.7	TSL:1	c.5175G>T	p.Leu1725Leu	synonymous	Exon 40 of 71	ENSP00000365823.3	Q96RL7-3
	VPS13A	ENST00000419472.1	TSL:1	c.48G>T	p.Leu16Leu	synonymous	Exon 1 of 7	ENSP00000414410.1	H0Y7P8

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 157 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00349

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00159

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00102 AC: 252 AN: 247478 AF XY: 0.000999

Gnomad AFR exome AF: 0.000190

Gnomad AMR exome AF: 0.000493

Gnomad ASJ exome AF: 0.0000997

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00351

Gnomad NFE exome AF: 0.00130

Gnomad OTH exome AF: 0.000661

GnomAD4 exome AF: 0.00100 AC: 1463 AN: 1461432 Hom.: 3 Cov.: 31 AF XY: 0.000978 AC XY: 711 AN XY: 727014

African (AFR) AF: 0.000239 AC: 8 AN: 33450

American (AMR) AF: 0.000470 AC: 21 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.000313 AC: 27 AN: 86254

European-Finnish (FIN) AF: 0.00294 AC: 157 AN: 53400

Middle Eastern (MID) AF: 0.000868 AC: 5 AN: 5758

European-Non Finnish (NFE) AF: 0.00107 AC: 1192 AN: 1111760

Other (OTH) AF: 0.000861 AC: 52 AN: 60370

GnomAD4 genome AF: 0.00103 AC: 157 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.00106 AC XY: 79 AN XY: 74422

African (AFR) AF: 0.000168 AC: 7 AN: 41550

American (AMR) AF: 0.000196 AC: 3 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00349 AC: 37 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00159 AC: 108 AN: 68016

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00119 Hom.: 0

Bravo AF: 0.000691

EpiCase AF: 0.00169

EpiControl AF: 0.00101

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	1	1	Chorea-acanthocytosis (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.81
DANN	Benign	0.57
PhyloP100		-2.2
PromoterAI		0.0052	Neutral
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs141528779; hg19: chr9-79933486;