NM_022916.6:c.1610-152delA

Variant names:

• chr12-122232578-AT-A
• rs35390554
• NM_022916.6:c.1610-152delA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_022916.6(VPS33A):​c.1610-152delA 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
• Publications: 0 publications found

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]

VPS33A Gene-Disease associations (from GenCC):

• mucopolysaccharidosis-plus syndrome

  Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen

ENSG00000256861 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022916.6. 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
	VPS33A	NM_022916.6	MANE Select	c.1610-152delA		intron	N/A	NP_075067.2
	VPS33A	NM_001351018.2		c.1577-152delA		intron	N/A	NP_001337947.1
	VPS33A	NM_001351019.2		c.1562-152delA		intron	N/A	NP_001337948.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS33A	ENST00000267199.9	TSL:1 MANE Select	c.1610-152delA		intron	N/A	ENSP00000267199.3	Q96AX1
	ENSG00000256861	ENST00000535844.1	TSL:2	n.1493-152delA		intron	N/A	ENSP00000454454.1	H3BMM5
	VPS33A	ENST00000536212.3	TSL:4	c.1757-152delA		intron	N/A	ENSP00000439255.3	F5H2X5

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

African (AFR) AF: 0.0442 AC: 913 AN: 20656

American (AMR) AF: 0.243 AC: 4330 AN: 17836

Ashkenazi Jewish (ASJ) AF: 0.232 AC: 3729 AN: 16096

East Asian (EAS) AF: 0.605 AC: 19516 AN: 32246

South Asian (SAS) AF: 0.328 AC: 16650 AN: 50734

European-Finnish (FIN) AF: 0.311 AC: 9590 AN: 30794

Middle Eastern (MID) AF: 0.200 AC: 563 AN: 2810

European-Non Finnish (NFE) AF: 0.251 AC: 168170 AN: 668846

Other (OTH) AF: 0.259 AC: 10281 AN: 39654

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

African (AFR) AF: 0.0525 AC: 2176 AN: 41430

American (AMR) AF: 0.220 AC: 3335 AN: 15174

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 809 AN: 3460

East Asian (EAS) AF: 0.623 AC: 3216 AN: 5166

South Asian (SAS) AF: 0.334 AC: 1603 AN: 4798

European-Finnish (FIN) AF: 0.325 AC: 3411 AN: 10496

Middle Eastern (MID) AF: 0.212 AC: 62 AN: 292

European-Non Finnish (NFE) AF: 0.260 AC: 17680 AN: 67872

Other (OTH) AF: 0.210 AC: 444 AN: 2112

Alfa AF: 0.122 Hom.: 215

Bravo AF: 0.204

Asia WGS AF: 0.381 AC: 1322 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.43
Mutation Taster		=100/0	polymorphism (auto)

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: rs35390554; hg19: chr12-122717125;