chr12-122232061-G-GA

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_022916.6(VPS33A):​c.*184dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0329 in 414,510 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.050 (0 hom.)
• Consequence: VPS33A NM_022916.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Variant has high frequency in the SAS (0.068) population. However there is too low homozygotes in high coverage region: (expected more than 112, got 0).

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.*184dupT		3_prime_UTR	Exon 13 of 13	NP_075067.2
	VPS33A	NM_001351018.2		c.*184dupT		3_prime_UTR	Exon 13 of 13	NP_001337947.1
	VPS33A	NM_001351019.2		c.*184dupT		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.*184dupT		3_prime_UTR	Exon 13 of 13	ENSP00000267199.3	Q96AX1
	ENSG00000256861	ENST00000535844.1	TSL:2	n.1594+264dupT		intron	N/A	ENSP00000454454.1	H3BMM5
	VPS33A	ENST00000536212.3	TSL:4	c.*184dupT		3_prime_UTR	Exon 14 of 14	ENSP00000439255.3	F5H2X5

Frequencies

GnomAD3 genomes AF: 0.000206 AC: 29 AN: 140508 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000777

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000283

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00122

Gnomad SAS AF: 0.000453

Gnomad FIN AF: 0.00109

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000784

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0497 AC: 13624 AN: 273930 Hom.: 0 Cov.: 4 AF XY: 0.0501 AC XY: 7088 AN XY: 141432

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

African (AFR) AF: 0.0285 AC: 190 AN: 6672

American (AMR) AF: 0.0559 AC: 399 AN: 7144

Ashkenazi Jewish (ASJ) AF: 0.0424 AC: 297 AN: 7008

East Asian (EAS) AF: 0.0343 AC: 497 AN: 14504

South Asian (SAS) AF: 0.0711 AC: 1392 AN: 19576

European-Finnish (FIN) AF: 0.0447 AC: 695 AN: 15560

Middle Eastern (MID) AF: 0.0510 AC: 51 AN: 1000

European-Non Finnish (NFE) AF: 0.0500 AC: 9401 AN: 188128

Other (OTH) AF: 0.0490 AC: 702 AN: 14338

⚠️ 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: 0.000206 AC: 29 AN: 140580 Hom.: 0 Cov.: 32 AF XY: 0.000191 AC XY: 13 AN XY: 68002

African (AFR) AF: 0.0000774 AC: 3 AN: 38738

American (AMR) AF: 0.000283 AC: 4 AN: 14146

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3328

East Asian (EAS) AF: 0.00122 AC: 6 AN: 4914

South Asian (SAS) AF: 0.000455 AC: 2 AN: 4400

European-Finnish (FIN) AF: 0.00109 AC: 9 AN: 8260

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

European-Non Finnish (NFE) AF: 0.0000784 AC: 5 AN: 63746

Other (OTH) AF: 0.00 AC: 0 AN: 1924

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.29
Mutation Taster		=100/0	polymorphism

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;