9-77316185-G-C

Variant names:

• chr9-77316185-G-C
• rs41289967
• NM_033305.3:c.4642G>C
• VPS13A p.Glu1548Gln

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033305.3(VPS13A):​c.4642G>C​(p.Glu1548Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,456,530 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. E1548K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: VPS13A NM_033305.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0870
• Publications: 7 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: Ambry Genetics, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03518817).

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.4642G>C	p.Glu1548Gln	missense	Exon 39 of 72	NP_150648.2	Q96RL7-1
	VPS13A	NM_001018037.2		c.4525G>C	p.Glu1509Gln	missense	Exon 38 of 71	NP_001018047.1	Q96RL7-3
	VPS13A	NM_015186.4		c.4642G>C	p.Glu1548Gln	missense	Exon 39 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.4642G>C	p.Glu1548Gln	missense	Exon 39 of 72	ENSP00000353422.3	Q96RL7-1
	VPS13A	ENST00000376636.7	TSL:1	c.4525G>C	p.Glu1509Gln	missense	Exon 38 of 71	ENSP00000365823.3	Q96RL7-3
	VPS13A	ENST00000643348.1		c.4642G>C	p.Glu1548Gln	missense	Exon 39 of 69	ENSP00000493592.1	Q96RL7-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249830 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456530 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724726

African (AFR) AF: 0.00 AC: 0 AN: 33324

American (AMR) AF: 0.0000224 AC: 1 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26054

East Asian (EAS) AF: 0.00 AC: 0 AN: 39568

South Asian (SAS) AF: 0.00 AC: 0 AN: 85968

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1107830

Other (OTH) AF: 0.00 AC: 0 AN: 60176

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 4

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	5.9
DANN	Benign	0.41
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.035	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.98	L
PhyloP100		0.087
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.041
Sift	Benign	0.40	T
Sift4G	Benign	0.50	T
Varity_R		0.084
gMVP		0.30
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs41289967;

hg19: chr9-79931101;