chr9-77307991-A-T

Variant names:

• chr9-77307991-A-T
• rs142058362
• NM_033305.3:c.4007A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_033305.3(VPS13A):​c.4007A>T​(p.His1336Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000326 in 1,602,988 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (2 hom.)
• Consequence: VPS13A NM_033305.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.09
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0053789914).
• BP6: Variant 9-77307991-A-T is Benign according to our data. Variant chr9-77307991-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 448861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00178 (271/152250) while in subpopulation AFR AF = 0.00628 (261/41546). AF 95% confidence interval is 0.00566. There are 2 homozygotes in GnomAd4. There are 134 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.4007A>T	p.His1336Leu	missense	Exon 35 of 72	NP_150648.2	Q96RL7-1
	VPS13A	NM_001018037.2		c.3890A>T	p.His1297Leu	missense	Exon 34 of 71	NP_001018047.1	Q96RL7-3
	VPS13A	NM_015186.4		c.4007A>T	p.His1336Leu	missense	Exon 35 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.4007A>T	p.His1336Leu	missense	Exon 35 of 72	ENSP00000353422.3	Q96RL7-1
	VPS13A	ENST00000376636.7	TSL:1	c.3890A>T	p.His1297Leu	missense	Exon 34 of 71	ENSP00000365823.3	Q96RL7-3
	VPS13A	ENST00000643348.1		c.4007A>T	p.His1336Leu	missense	Exon 35 of 69	ENSP00000493592.1	Q96RL7-2

Frequencies

GnomAD3 genomes AF: 0.00178 AC: 271 AN: 152132 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00630

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000502 AC: 126 AN: 250952 AF XY: 0.000339

Gnomad AFR exome AF: 0.00739

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000174 AC: 252 AN: 1450738 Hom.: 2 Cov.: 32 AF XY: 0.000166 AC XY: 120 AN XY: 722484

African (AFR) AF: 0.00646 AC: 215 AN: 33298

American (AMR) AF: 0.000201 AC: 9 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39542

South Asian (SAS) AF: 0.00 AC: 0 AN: 85962

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5746

European-Non Finnish (NFE) AF: 0.00000363 AC: 4 AN: 1101998

Other (OTH) AF: 0.000367 AC: 22 AN: 60020

GnomAD4 genome AF: 0.00178 AC: 271 AN: 152250 Hom.: 2 Cov.: 32 AF XY: 0.00180 AC XY: 134 AN XY: 74454

African (AFR) AF: 0.00628 AC: 261 AN: 41546

American (AMR) AF: 0.000458 AC: 7 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.0000901 Hom.: 0

Bravo AF: 0.00199

ESP6500AA AF: 0.00567 AC: 25

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000560 AC: 68

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Chorea-acanthocytosis (2)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	VPS13A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	20
DANN	Benign	0.92
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.096
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.1
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.052
Sift	Benign	0.66	T
Sift4G	Benign	0.66	T
Polyphen		0.054	B
Vest4		0.37
MVP		0.44
MPC		0.16
ClinPred		0.025	T
GERP RS		4.6
Varity_R		0.11
gMVP		0.44
Mutation Taster		=99/1	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: rs142058362; hg19: chr9-79922907;