chr9-77252265-G-T

Position:

• chr9-77252265-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033305.3(VPS13A):​c.2201G>T​(p.Ser734Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. S734N) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: VPS13A NM_033305.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.738

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.083658665).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS13A	NM_033305.3	c.2201G>T	p.Ser734Ile	missense_variant	22/72	ENST00000360280.8	NP_150648.2
VPS13A	NM_001018037.2	c.2201G>T	p.Ser734Ile	missense_variant	22/71		NP_001018047.1
VPS13A	NM_015186.4	c.2201G>T	p.Ser734Ile	missense_variant	22/69		NP_056001.1
VPS13A	NM_001018038.3	c.2201G>T	p.Ser734Ile	missense_variant	22/69		NP_001018048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS13A	ENST00000360280.8	c.2201G>T	p.Ser734Ile	missense_variant	22/72	1	NM_033305.3	ENSP00000353422	P4
VPS13A	ENST00000376636.7	c.2201G>T	p.Ser734Ile	missense_variant	22/71	1		ENSP00000365823
VPS13A	ENST00000643348.1	c.2201G>T	p.Ser734Ile	missense_variant	22/69			ENSP00000493592
VPS13A	ENST00000645632.1	c.2201G>T	p.Ser734Ile	missense_variant	22/69			ENSP00000496361	A1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74336

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	.;.;T;.;.;.;T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.81	.;T;.;.;T;T;T
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.084	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N;N;N;N;N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.1	N;N;N;N;.;.;.
REVEL	Benign	0.016
Sift	Benign	0.13	T;T;T;T;.;.;.
Sift4G	Benign	0.084	T;T;T;D;.;.;.
Polyphen		0.045	B;B;B;B;B;B;B
Vest4		0.26
MutPred		0.44		Loss of disorder (P = 0.0202);Loss of disorder (P = 0.0202);Loss of disorder (P = 0.0202);Loss of disorder (P = 0.0202);Loss of disorder (P = 0.0202);Loss of disorder (P = 0.0202);Loss of disorder (P = 0.0202);
MVP		0.36
MPC		0.17
ClinPred		0.086	T
GERP RS		-0.073
Varity_R		0.057
gMVP		0.20

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: rs117320408; hg19: chr9-79867181;