12-122232578-AT-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_022916.6(VPS33A):c.1610-152del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.259 in 1,031,382 control chromosomes in the GnomAD database, including 39,478 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.22 (4791 hom., cov: 27)
  • Exomes 𝑓: 0.27 (34687 hom.)
• Consequence: VPS33A NM_022916.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.427

Genes affected

VPS33A (HGNC:18179): (VPS33A core subunit of CORVET and HOPS complexes) This gene encodes a tethering protein and a core subunit of the homotypic fusion and protein sorting (HOPS) complex. The HOPS complex and a second endosomal tethering complex called the class C core vacuole/endosome tethering (CORVET) complex, perform diverse functions in endocytosis including membrane tethering, RabGTPase interaction, activation and proofreading of synaptic-soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) assembly to drive membrane fusion, and endosome-to-cytoskeleton attachment. The HOPS complex controls endosome maturation as well as endosome traffic to the lysosome. This complex is essential for vacuolar fusion and is required for adaptor protein complex 3-dependent transport from the golgi to the vacuole. The encoded protein belongs to the Sec1/Munc18 (SM) family of SNARE-mediated membrane fusion regulators. Naturally occurring mutations in this gene are associated with a novel mucopolysaccharidosis-like disease. [provided by RefSeq, Apr 2017]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 12-122232578-AT-A is Benign according to our data. Variant chr12-122232578-AT-A is described in ClinVar as [Benign]. Clinvar id is 1269268.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.605 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS33A	NM_022916.6	c.1610-152del		intron_variant		ENST00000267199.9
VPS33A	NM_001351018.2	c.1577-152del		intron_variant
VPS33A	NM_001351019.2	c.1562-152del		intron_variant
VPS33A	NM_001351020.2	c.1289-152del		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS33A	ENST00000267199.9	c.1610-152del		intron_variant		1	NM_022916.6	P1
VPS33A	ENST00000643696.1	c.1733-152del		intron_variant
VPS33A	ENST00000543633.5	c.*1571-152del		intron_variant, NMD_transcript_variant		5
VPS33A	ENST00000544349.6	c.*1589-152del		intron_variant, NMD_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.217 AC: 32928 AN: 151594 Hom.: 4796 Cov.: 27

Gnomad AFR AF: 0.0526

Gnomad AMI AF: 0.201

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.623

Gnomad SAS AF: 0.334

Gnomad FIN AF: 0.325

Gnomad MID AF: 0.204

Gnomad NFE AF: 0.261

Gnomad OTH AF: 0.208

GnomAD4 exome AF: 0.266 AC: 233742 AN: 879672 Hom.: 34687 AF XY: 0.269 AC XY: 117869 AN XY: 438206

Gnomad4 AFR exome AF: 0.0442

Gnomad4 AMR exome AF: 0.243

Gnomad4 ASJ exome AF: 0.232

Gnomad4 EAS exome AF: 0.605

Gnomad4 SAS exome AF: 0.328

Gnomad4 FIN exome AF: 0.311

Gnomad4 NFE exome AF: 0.251

Gnomad4 OTH exome AF: 0.259

GnomAD4 genome AF: 0.217 AC: 32919 AN: 151710 Hom.: 4791 Cov.: 27 AF XY: 0.225 AC XY: 16693 AN XY: 74108

Gnomad4 AFR AF: 0.0525

Gnomad4 AMR AF: 0.220

Gnomad4 ASJ AF: 0.234

Gnomad4 EAS AF: 0.623

Gnomad4 SAS AF: 0.334

Gnomad4 FIN AF: 0.325

Gnomad4 NFE AF: 0.260

Gnomad4 OTH AF: 0.210

Alfa AF: 0.122 Hom.: 215

Bravo AF: 0.204

Asia WGS AF: 0.381 AC: 1322 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

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: rs35390554; hg19: chr12-122717125;