12-122232578-ATTTTT-ATTTTTT

Variant names:

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

Variant summary

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

The NM_022916.6(VPS33A):​c.1610-152dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000169 in 1,037,856 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 0.0000066 (0 hom., cov: 27)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: VPS33A NM_022916.6 intron
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

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.1610-152dupA		intron	N/A	NP_075067.2
	VPS33A	NM_001351018.2		c.1577-152dupA		intron	N/A	NP_001337947.1
	VPS33A	NM_001351019.2		c.1562-152dupA		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.1610-152_1610-151insA		intron	N/A	ENSP00000267199.3	Q96AX1
	ENSG00000256861	ENST00000535844.1	TSL:2	n.1493-152_1493-151insA		intron	N/A	ENSP00000454454.1	H3BMM5
	VPS33A	ENST00000536212.3	TSL:4	c.1757-152_1757-151insA		intron	N/A	ENSP00000439255.3	F5H2X5

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151640 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000196 AC: 174 AN: 886216 Hom.: 0 AF XY: 0.000193 AC XY: 85 AN XY: 441514

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

African (AFR) AF: 0.000239 AC: 5 AN: 20928

American (AMR) AF: 0.000111 AC: 2 AN: 17994

Ashkenazi Jewish (ASJ) AF: 0.000246 AC: 4 AN: 16248

East Asian (EAS) AF: 0.00 AC: 0 AN: 32332

South Asian (SAS) AF: 0.0000586 AC: 3 AN: 51174

European-Finnish (FIN) AF: 0.0000645 AC: 2 AN: 31006

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2824

European-Non Finnish (NFE) AF: 0.000230 AC: 155 AN: 673728

Other (OTH) AF: 0.0000750 AC: 3 AN: 39982

⚠️ 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: 0.00000659 AC: 1 AN: 151640 Hom.: 0 Cov.: 27 AF XY: 0.0000135 AC XY: 1 AN XY: 74010

African (AFR) AF: 0.00 AC: 0 AN: 41314

American (AMR) AF: 0.00 AC: 0 AN: 15166

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10508

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67892

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 215

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.43

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;