rs145346590

Variant names:

• chr9-77276211-A-G
• rs145346590
• NM_033305.3:c.2814A>G
• VPS13A p.Pro938Pro

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_033305.3(VPS13A):​c.2814A>G​(p.Pro938Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00068 in 1,605,906 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).

• Frequency:
  • Genomes: 𝑓 0.00089 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (3 hom.)
• Consequence: VPS13A NM_033305.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.183
• Publications: 0 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: Orphanet, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 9-77276211-A-G is Benign according to our data. Variant chr9-77276211-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 586928.
• BP7: Synonymous conserved (PhyloP=0.183 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000893 (136/152304) while in subpopulation AMR AF = 0.00464 (71/15302). AF 95% confidence interval is 0.00377. There are 0 homozygotes in GnomAd4. There are 79 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• 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.2814A>G	p.Pro938Pro	synonymous	Exon 26 of 72	NP_150648.2	Q96RL7-1
	VPS13A	NM_001018037.2		c.2814A>G	p.Pro938Pro	synonymous	Exon 26 of 71	NP_001018047.1	Q96RL7-3
	VPS13A	NM_015186.4		c.2814A>G	p.Pro938Pro	synonymous	Exon 26 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.2814A>G	p.Pro938Pro	synonymous	Exon 26 of 72	ENSP00000353422.3	Q96RL7-1
	VPS13A	ENST00000376636.7	TSL:1	c.2814A>G	p.Pro938Pro	synonymous	Exon 26 of 71	ENSP00000365823.3	Q96RL7-3
	VPS13A	ENST00000643348.1		c.2814A>G	p.Pro938Pro	synonymous	Exon 26 of 69	ENSP00000493592.1	Q96RL7-2

Frequencies

GnomAD3 genomes AF: 0.000894 AC: 136 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00465

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: 0.000794

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000576 AC: 143 AN: 248200 AF XY: 0.000507

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00217

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000934

Gnomad NFE exome AF: 0.000559

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000658 AC: 956 AN: 1453602 Hom.: 3 Cov.: 31 AF XY: 0.000637 AC XY: 460 AN XY: 722402

African (AFR) AF: 0.000150 AC: 5 AN: 33370

American (AMR) AF: 0.00234 AC: 104 AN: 44428

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26000

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39352

South Asian (SAS) AF: 0.0000240 AC: 2 AN: 83440

European-Finnish (FIN) AF: 0.0000378 AC: 2 AN: 52846

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5666

European-Non Finnish (NFE) AF: 0.000724 AC: 803 AN: 1108488

Other (OTH) AF: 0.000633 AC: 38 AN: 60012

GnomAD4 genome AF: 0.000893 AC: 136 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.00106 AC XY: 79 AN XY: 74472

African (AFR) AF: 0.000120 AC: 5 AN: 41564

American (AMR) AF: 0.00464 AC: 71 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000794 AC: 54 AN: 68020

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.000536 Hom.: 0

Bravo AF: 0.000967

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	1	Chorea-acanthocytosis (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	7.2
DANN	Benign	0.75
PhyloP100		0.18
Mutation Taster		=100/0	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs145346590;

hg19: chr9-79891127;