9-77205394-T-C

Variant names:

• chr9-77205394-T-C
• rs119477052
• NM_033305.3:c.269T>C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_033305.3(VPS13A):​c.269T>C​(p.Ile90Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000766 in 1,435,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I90K) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000070 (0 hom.)
• Consequence: VPS13A NM_033305.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.37

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-77205394-T-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.797

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13A	NM_033305.3	c.269T>C	p.Ile90Thr	missense_variant	Exon 4 of 72	ENST00000360280.8	NP_150648.2
VPS13A	NM_001018037.2	c.269T>C	p.Ile90Thr	missense_variant	Exon 4 of 71		NP_001018047.1
VPS13A	NM_015186.4	c.269T>C	p.Ile90Thr	missense_variant	Exon 4 of 69		NP_056001.1
VPS13A	NM_001018038.3	c.269T>C	p.Ile90Thr	missense_variant	Exon 4 of 69		NP_001018048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS13A	ENST00000360280.8	c.269T>C	p.Ile90Thr	missense_variant	Exon 4 of 72	1	NM_033305.3	ENSP00000353422.3
VPS13A	ENST00000376636.7	c.269T>C	p.Ile90Thr	missense_variant	Exon 4 of 71	1		ENSP00000365823.3
VPS13A	ENST00000643348.1	c.269T>C	p.Ile90Thr	missense_variant	Exon 4 of 69			ENSP00000493592.1
VPS13A	ENST00000645632.1	c.269T>C	p.Ile90Thr	missense_variant	Exon 4 of 69			ENSP00000496361.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151936 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000205 AC: 4 AN: 195514 Hom.: 0 AF XY: 0.0000279 AC XY: 3 AN XY: 107452

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000238

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000105

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000701 AC: 9 AN: 1283950 Hom.: 0 Cov.: 23 AF XY: 0.00000944 AC XY: 6 AN XY: 635604

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000852

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000594

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151936 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74242

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000384

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000247 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	.;.;D;.;.;.;D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	.;D;.;.;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Uncertain	2.3	M;M;M;M;M;M;M
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.9	D;D;D;D;.;.;.
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0090	D;D;D;D;.;.;.
Sift4G	Uncertain	0.012	D;D;D;D;.;.;.
Polyphen		0.99	D;D;D;D;D;D;D
Vest4		0.87
MutPred		0.63		Loss of stability (P = 0.0271);Loss of stability (P = 0.0271);Loss of stability (P = 0.0271);Loss of stability (P = 0.0271);Loss of stability (P = 0.0271);Loss of stability (P = 0.0271);Loss of stability (P = 0.0271);
MVP		0.93
MPC		0.61
ClinPred		0.83	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.76

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

LitVar

Other links and lift over

dbSNP: rs119477052; hg19: chr9-79820310;