15-90999318-GTTTT-GTTTTTT

Variant names:

• chr15-90999318-G-GTT
• rs199831273
• NM_018668.5:c.1775-266_1775-265dupAA

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_018668.5(VPS33B):​c.1775-266_1775-265dupAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00683 in 476,810 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 0.00018 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0098 (0 hom.)
• Consequence: VPS33B NM_018668.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.24

Genes affected

VPS33B (HGNC:12712): (VPS33B late endosome and lysosome associated) Vesicle mediated protein sorting plays an important role in segregation of intracellular molecules into distinct organelles. Genetic studies in yeast have identified more than 40 vacuolar protein sorting (VPS) genes involved in vesicle transport to vacuoles. This gene is a member of the Sec-1 domain family, and encodes the human ortholog of rat Vps33b which is homologous to the yeast class C Vps33 protein. The mammalian class C vacuolar protein sorting proteins are predominantly associated with late endosomes/lysosomes, and like their yeast counterparts, may mediate vesicle trafficking steps in the endosome/lysosome pathway. Mutations in this gene are associated with arthrogryposis-renal dysfunction-cholestasis syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

ENSG00000284946 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0595 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS33B	NM_018668.5	c.1775-266_1775-265dupAA		intron_variant	Intron 22 of 22	ENST00000333371.8	NP_061138.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS33B	ENST00000333371.8	c.1775-265_1775-264insAA		intron_variant	Intron 22 of 22	1	NM_018668.5	ENSP00000327650.4
ENSG00000284946	ENST00000643536.1	n.1774+358_1774+359insAA		intron_variant	Intron 22 of 34			ENSP00000494429.1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 27 AN: 146620 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.000225

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000204

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00199

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000110

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000602

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00978 AC: 3229 AN: 330150 Hom.: 0 Cov.: 0 AF XY: 0.00975 AC XY: 1710 AN XY: 175308

Gnomad4 AFR exome AF: 0.00618

Gnomad4 AMR exome AF: 0.0224

Gnomad4 ASJ exome AF: 0.00394

Gnomad4 EAS exome AF: 0.0624

Gnomad4 SAS exome AF: 0.0110

Gnomad4 FIN exome AF: 0.00399

Gnomad4 NFE exome AF: 0.00466

Gnomad4 OTH exome AF: 0.00748

GnomAD4 genome AF: 0.000184 AC: 27 AN: 146660 Hom.: 0 Cov.: 29 AF XY: 0.000168 AC XY: 12 AN XY: 71304

Gnomad4 AFR AF: 0.000224

Gnomad4 AMR AF: 0.000203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00199

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000110

Gnomad4 NFE AF: 0.0000602

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs199831273; hg19: chr15-91542548;