12-122232061-GAAA-GAAAAAAAAAAA

Variant names:

• chr12-122232061-G-GAAAAAAAA
• rs370160099
• NM_022916.6:c.*177_*184dupTTTTTTTT

Variant summary

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

The NM_022916.6(VPS33A):​c.*177_*184dupTTTTTTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• 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: 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.*177_*184dupTTTTTTTT		3_prime_UTR	Exon 13 of 13	NP_075067.2
	VPS33A	NM_001351018.2		c.*177_*184dupTTTTTTTT		3_prime_UTR	Exon 13 of 13	NP_001337947.1
	VPS33A	NM_001351019.2		c.*177_*184dupTTTTTTTT		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.*177_*184dupTTTTTTTT		3_prime_UTR	Exon 13 of 13	ENSP00000267199.3	Q96AX1
	ENSG00000256861	ENST00000535844.1	TSL:2	n.1594+257_1594+264dupTTTTTTTT		intron	N/A	ENSP00000454454.1	H3BMM5
	VPS33A	ENST00000536212.3	TSL:4	c.*177_*184dupTTTTTTTT		3_prime_UTR	Exon 14 of 14	ENSP00000439255.3	F5H2X5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 4

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000564 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.29

Splicing

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

Other links and lift over

dbSNP: rs370160099; hg19: chr12-122716608;