rs35390554

Variant names:

• chr12-122232578-ATTTTT-A
• rs35390554
• NM_022916.6:c.1610-156_1610-152delAAAAA

Your query was ambiguous. Multiple possible variants found:

• chr12-122232578-ATTTTT-A
• chr12-122232578-ATTTTT-ATTT
• chr12-122232578-ATTTTT-ATTTT
• chr12-122232578-ATTTTT-ATTTTTT

Variant summary

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

The NM_022916.6(VPS33A):​c.1610-156_1610-152delAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000113 in 886,844 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: not found (cov: 27)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: VPS33A NM_022916.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.16
• 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: Very rare variant in population databases, with high coverage

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.1610-156_1610-152delAAAAA		intron	N/A	NP_075067.2
	VPS33A	NM_001351018.2		c.1577-156_1577-152delAAAAA		intron	N/A	NP_001337947.1
	VPS33A	NM_001351019.2		c.1562-156_1562-152delAAAAA		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.1610-156_1610-152delAAAAA		intron	N/A	ENSP00000267199.3	Q96AX1
	ENSG00000256861	ENST00000535844.1	TSL:2	n.1493-156_1493-152delAAAAA		intron	N/A	ENSP00000454454.1	H3BMM5
	VPS33A	ENST00000536212.3	TSL:4	c.1757-156_1757-152delAAAAA		intron	N/A	ENSP00000439255.3	F5H2X5

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome AF: 0.00000113 AC: 1 AN: 886844 Hom.: 0 AF XY: 0.00000226 AC XY: 1 AN XY: 441802

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

African (AFR) AF: 0.00 AC: 0 AN: 20946

American (AMR) AF: 0.00 AC: 0 AN: 18010

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16264

East Asian (EAS) AF: 0.00 AC: 0 AN: 32338

South Asian (SAS) AF: 0.00 AC: 0 AN: 51200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31018

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

European-Non Finnish (NFE) AF: 0.00000148 AC: 1 AN: 674242

Other (OTH) AF: 0.00 AC: 0 AN: 40002

⚠️ 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 Cov.: 27

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35390554; hg19: chr12-122717125;