NM_022916.6:c.*184delT

Variant names:

• chr12-122232061-GA-G
• rs370160099
• NM_022916.6:c.*184delT

Variant summary

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

The NM_022916.6(VPS33A):​c.*184delT 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
• 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 12-122232061-GA-G is Benign according to our data. Variant chr12-122232061-GA-G is described in ClinVar as Benign. ClinVar VariationId 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.

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.*184delT		3_prime_UTR	Exon 13 of 13	NP_075067.2
	VPS33A	NM_001351018.2		c.*184delT		3_prime_UTR	Exon 13 of 13	NP_001337947.1
	VPS33A	NM_001351019.2		c.*184delT		3_prime_UTR	Exon 13 of 13	NP_001337948.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS33A	ENST00000267199.9	TSL:1 MANE Select	c.*184delT		3_prime_UTR	Exon 13 of 13	ENSP00000267199.3	Q96AX1
	ENSG00000256861	ENST00000535844.1	TSL:2	n.1594+264delT		intron	N/A	ENSP00000454454.1	H3BMM5
	VPS33A	ENST00000536212.3	TSL:4	c.*184delT		3_prime_UTR	Exon 14 of 14	ENSP00000439255.3	F5H2X5

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

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

African (AFR) AF: 0.195 AC: 1333 AN: 6836

American (AMR) AF: 0.0613 AC: 440 AN: 7182

Ashkenazi Jewish (ASJ) AF: 0.0755 AC: 540 AN: 7148

East Asian (EAS) AF: 0.0271 AC: 398 AN: 14702

South Asian (SAS) AF: 0.0662 AC: 1278 AN: 19298

European-Finnish (FIN) AF: 0.0353 AC: 558 AN: 15808

Middle Eastern (MID) AF: 0.0417 AC: 44 AN: 1054

European-Non Finnish (NFE) AF: 0.0401 AC: 7586 AN: 189320

Other (OTH) AF: 0.0560 AC: 819 AN: 14618

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.138 AC: 5361 AN: 38718

American (AMR) AF: 0.0169 AC: 239 AN: 14136

Ashkenazi Jewish (ASJ) AF: 0.0303 AC: 101 AN: 3328

East Asian (EAS) AF: 0.000814 AC: 4 AN: 4914

South Asian (SAS) AF: 0.000910 AC: 4 AN: 4398

European-Finnish (FIN) AF: 0.000850 AC: 7 AN: 8234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.00108 AC: 69 AN: 63714

Other (OTH) AF: 0.0302 AC: 58 AN: 1922

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0441

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		0.29
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: rs370160099; hg19: chr12-122716608; COSMIC: COSV57356166; COSMIC: COSV57356166;