rs2131029946

Variant names:

• chr9-77177705-A-T
• rs2131029946
• NM_033305.3:c.1A>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_033305.3(VPS13A):​c.1A>T​(p.Met1?) variant causes a initiator codon change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: VPS13A NM_033305.3 initiator_codon
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.61
• 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-AS1 (HGNC:44167): (VPS13A antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 17 pathogenic variants. Next in-frame start position is after 108 codons. Genomic position: 77206016. Lost 0.034 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-77177705-A-T is Pathogenic according to our data. Variant chr9-77177705-A-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1698814.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1A>T	p.Met1?	initiator_codon	Exon 1 of 72	NP_150648.2	Q96RL7-1
	VPS13A	NM_001018037.2		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 71	NP_001018047.1	Q96RL7-3
	VPS13A	NM_015186.4		c.1A>T	p.Met1?	initiator_codon	Exon 1 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.1A>T	p.Met1?	initiator_codon	Exon 1 of 72	ENSP00000353422.3	Q96RL7-1
	VPS13A	ENST00000376636.7	TSL:1	c.1A>T	p.Met1?	initiator_codon	Exon 1 of 71	ENSP00000365823.3	Q96RL7-3
	VPS13A	ENST00000643348.1		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 69	ENSP00000493592.1	Q96RL7-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Chorea-acanthocytosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	23
DANN	Benign	0.85
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-0.031
Eigen_PC	Benign	-0.087
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.52	T
PhyloP100		5.6
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.83
MutPred		1.0		Loss of disorder (P = 0.1049)
MVP		0.77
ClinPred		1.0	D
GERP RS		3.6
PromoterAI		-0.20	Neutral
Varity_R		0.92
gMVP		0.79
Mutation Taster		=10/190	disease causing

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: rs2131029946; hg19: chr9-79792621;