chr15-90999061-A-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM2BP4_StrongBP6_ModerateBS1

The NM_018668.5(VPS33B):​c.1775-7T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000378 in 1,613,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

VPS33B
NM_018668.5 splice_region, splice_polypyrimidine_tract, intron

Scores

2
Splicing: ADA: 0.00002614
2

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.95
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.79).
BP6
Variant 15-90999061-A-G is Benign according to our data. Variant chr15-90999061-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 722711.Status of the report is criteria_provided_single_submitter, 1 stars.
BS1
Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000376 (55/1461664) while in subpopulation AMR AF= 0.00123 (55/44682). AF 95% confidence interval is 0.000971. There are 0 homozygotes in gnomad4_exome. There are 24 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
VPS33BNM_018668.5 linkuse as main transcriptc.1775-7T>C splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant ENST00000333371.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
VPS33BENST00000333371.8 linkuse as main transcriptc.1775-7T>C splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant 1 NM_018668.5 P1Q9H267-1
VPS33BENST00000535906.1 linkuse as main transcriptc.1694-7T>C splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant 2
VPS33BENST00000574755.5 linkuse as main transcriptc.*1470-7T>C splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant 2
VPS33BENST00000557470.5 linkuse as main transcriptn.148-7T>C splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant 5

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152170
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000393
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000196
AC:
49
AN:
250376
Hom.:
0
AF XY:
0.000148
AC XY:
20
AN XY:
135396
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00142
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000376
AC:
55
AN:
1461664
Hom.:
0
Cov.:
30
AF XY:
0.0000330
AC XY:
24
AN XY:
727094
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00123
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152288
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74460
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000392
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000604

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingInvitaeJun 23, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.79
CADD
Benign
10
DANN
Benign
0.68

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000026
dbscSNV1_RF
Benign
0.0040
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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs544401242; hg19: chr15-91542291; API