9-77177524-G-T

Variant names:

• chr9-77177524-G-T
• rs117488726
• ENST00000376636.7:c.-181G>T

Variant summary

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

The ENST00000376636.7(VPS13A):​c.-181G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000221 in 452,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: VPS13A ENST00000376636.7 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0420
• 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-AS1 (HGNC:44167): (VPS13A antisense RNA 1)

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 (BayesDel_noAF=-0.64).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS13A	NM_033305.3	c.-181G>T		upstream_gene_variant		ENST00000360280.8	NP_150648.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS13A	ENST00000360280.8	c.-181G>T		upstream_gene_variant		1	NM_033305.3	ENSP00000353422.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000221 AC: 1 AN: 452578 Hom.: 0 Cov.: 5 AF XY: 0.00000412 AC XY: 1 AN XY: 242678

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 12014

American (AMR) AF: 0.00 AC: 0 AN: 24454

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13746

East Asian (EAS) AF: 0.00 AC: 0 AN: 28146

South Asian (SAS) AF: 0.00 AC: 0 AN: 50664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27546

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1926

European-Non Finnish (NFE) AF: 0.00000372 AC: 1 AN: 269004

Other (OTH) AF: 0.00 AC: 0 AN: 25078

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	8.1
DANN	Benign	0.80
PhyloP100		0.042
PromoterAI		-0.21	Neutral

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: rs117488726; hg19: chr9-79792440; COSMIC: COSV62429104; COSMIC: COSV62429104;