9-77177738-A-C

Variant names:

• chr9-77177738-A-C
• NM_033305.3:c.34A>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_033305.3(VPS13A):​c.34A>C​(p.Asn12His) variant causes a missense 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: VPS13A NM_033305.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.78

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.841

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13A	NM_033305.3	c.34A>C	p.Asn12His	missense_variant	Exon 1 of 72	ENST00000360280.8	NP_150648.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS13A	ENST00000360280.8	c.34A>C	p.Asn12His	missense_variant	Exon 1 of 72	1	NM_033305.3	ENSP00000353422.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Dec 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.34A>C (p.N12H) alteration is located in exon 1 (coding exon 1) of the VPS13A gene. This alteration results from a A to C substitution at nucleotide position 34, causing the asparagine (N) at amino acid position 12 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	.;.;D;.;.;.;D
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.95	.;D;.;.;D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.84	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Pathogenic	3.6	H;H;H;H;H;H;H
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.6	D;D;D;D;.;.;.
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;D;D;D;.;.;.
Sift4G	Uncertain	0.0020	D;D;D;D;.;.;.
Polyphen		1.0	D;D;D;D;D;D;D
Vest4		0.55
MutPred		0.47		Loss of stability (P = 0.2313);Loss of stability (P = 0.2313);Loss of stability (P = 0.2313);Loss of stability (P = 0.2313);Loss of stability (P = 0.2313);Loss of stability (P = 0.2313);Loss of stability (P = 0.2313);
MVP		0.86
MPC		3.5
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.88

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-79792654;