12-122232061-GA-G

Variant summary

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

The NM_022916.6(VPS33A):c.*184del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0452 in 416,454 control chromosomes in the GnomAD database, including 436 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.042 (366 hom., cov: 32)
  • Exomes 𝑓: 0.047 (70 hom.)
• Consequence: VPS33A NM_022916.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.294

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 12-122232061-GA-G is Benign according to our data. Variant chr12-122232061-GA-G is described in ClinVar as [Benign]. Clinvar id is 1182303.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS33A	NM_022916.6	c.*184del		3_prime_UTR_variant	13/13	ENST00000267199.9
VPS33A	NM_001351018.2	c.*184del		3_prime_UTR_variant	13/13
VPS33A	NM_001351019.2	c.*184del		3_prime_UTR_variant	13/13
VPS33A	NM_001351020.2	c.*184del		3_prime_UTR_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS33A	ENST00000267199.9	c.*184del		3_prime_UTR_variant	13/13	1	NM_022916.6	P1
VPS33A	ENST00000643696.1	c.*184del		3_prime_UTR_variant	14/14
VPS33A	ENST00000544349.6	c.*1954del		3_prime_UTR_variant, NMD_transcript_variant	14/14	2

Frequencies

GnomAD3 genomes AF: 0.0415 AC: 5825 AN: 140416 Hom.: 364 Cov.: 32

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0169

Gnomad ASJ AF: 0.0303

Gnomad EAS AF: 0.000811

Gnomad SAS AF: 0.00113

Gnomad FIN AF: 0.000850

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00108

Gnomad OTH AF: 0.0304

GnomAD4 exome AF: 0.0471 AC: 12996 AN: 275966 Hom.: 70 Cov.: 4 AF XY: 0.0478 AC XY: 6809 AN XY: 142542

Gnomad4 AFR exome AF: 0.195

Gnomad4 AMR exome AF: 0.0613

Gnomad4 ASJ exome AF: 0.0755

Gnomad4 EAS exome AF: 0.0271

Gnomad4 SAS exome AF: 0.0662

Gnomad4 FIN exome AF: 0.0353

Gnomad4 NFE exome AF: 0.0401

Gnomad4 OTH exome AF: 0.0560

GnomAD4 genome AF: 0.0416 AC: 5843 AN: 140488 Hom.: 366 Cov.: 32 AF XY: 0.0406 AC XY: 2761 AN XY: 67950

Gnomad4 AFR AF: 0.138

Gnomad4 AMR AF: 0.0169

Gnomad4 ASJ AF: 0.0303

Gnomad4 EAS AF: 0.000814

Gnomad4 SAS AF: 0.000910

Gnomad4 FIN AF: 0.000850

Gnomad4 NFE AF: 0.00108

Gnomad4 OTH AF: 0.0302

Bravo AF: 0.0441

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

Aug 13, 2019

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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: rs370160099; hg19: chr12-122716608;