9-77276145-A-T

Variant names:

• chr9-77276145-A-T
• rs73466090
• NM_033305.3:c.2748A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033305.3(VPS13A):​c.2748A>T​(p.Glu916Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 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. E916A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VPS13A NM_033305.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.637
• 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, Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09266704).

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.2748A>T	p.Glu916Asp	missense	Exon 26 of 72	NP_150648.2
	VPS13A	NM_001018037.2		c.2748A>T	p.Glu916Asp	missense	Exon 26 of 71	NP_001018047.1
	VPS13A	NM_015186.4		c.2748A>T	p.Glu916Asp	missense	Exon 26 of 69	NP_056001.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS13A	ENST00000360280.8	TSL:1 MANE Select	c.2748A>T	p.Glu916Asp	missense	Exon 26 of 72	ENSP00000353422.3
	VPS13A	ENST00000376636.7	TSL:1	c.2748A>T	p.Glu916Asp	missense	Exon 26 of 71	ENSP00000365823.3
	VPS13A	ENST00000643348.1		c.2748A>T	p.Glu916Asp	missense	Exon 26 of 69	ENSP00000493592.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.96
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.64
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.10
Sift	Benign	0.14	T
Sift4G	Benign	0.11	T
Polyphen		0.075	B
Vest4		0.15
MutPred		0.49		Loss of sheet (P = 0.1398)
MVP		0.39
MPC		0.12
ClinPred		0.12	T
GERP RS		-5.0
Varity_R		0.049
gMVP		0.68
Mutation Taster		=95/5	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

Other links and lift over

dbSNP: rs73466090; hg19: chr9-79891061;