chr15-91000531-C-T

Variant names:

• chr15-91000531-C-T
• rs11073964
• NM_018668.5:c.1540G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018668.5(VPS33B):​c.1540G>A​(p.Gly514Ser) variant causes a missense change. The variant allele was found at a frequency of 0.466 in 1,613,018 control chromosomes in the GnomAD database, including 197,039 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G514R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.59 (30537 hom., cov: 31)
  • Exomes 𝑓: 0.45 (166502 hom.)
• Consequence: VPS33B NM_018668.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 4.34
• Publications: 61 publications found

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:):

VPS33B-DT (HGNC:51413): (VPS33B divergent transcript)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.6257657E-6).
• BP6: Variant 15-91000531-C-T is Benign according to our data. Variant chr15-91000531-C-T is described in ClinVar as Benign. ClinVar VariationId is 261041.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.969 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018668.5. 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
	VPS33B	NM_018668.5	MANE Select	c.1540G>A	p.Gly514Ser	missense	Exon 20 of 23	NP_061138.3
	VPS33B	NM_001289148.1		c.1459G>A	p.Gly487Ser	missense	Exon 19 of 22	NP_001276077.1	B7Z1N4
	VPS33B	NM_001289149.1		c.1267G>A	p.Gly423Ser	missense	Exon 19 of 22	NP_001276078.1	Q9H267-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS33B	ENST00000333371.8	TSL:1 MANE Select	c.1540G>A	p.Gly514Ser	missense	Exon 20 of 23	ENSP00000327650.4	Q9H267-1
	ENSG00000284946	ENST00000643536.1		n.1540G>A		non_coding_transcript_exon	Exon 20 of 35	ENSP00000494429.1	A0A2R8YDQ0
	VPS33B	ENST00000853125.1		c.1555G>A	p.Gly519Ser	missense	Exon 20 of 23	ENSP00000523184.1

Frequencies

GnomAD3 genomes AF: 0.592 AC: 89878 AN: 151930 Hom.: 30470 Cov.: 31

Gnomad AFR AF: 0.882

Gnomad AMI AF: 0.498

Gnomad AMR AF: 0.647

Gnomad ASJ AF: 0.430

Gnomad EAS AF: 0.992

Gnomad SAS AF: 0.699

Gnomad FIN AF: 0.413

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.402

Gnomad OTH AF: 0.579

GnomAD2 exomes AF: 0.564 AC: 141763 AN: 251182 AF XY: 0.550

Gnomad AFR exome AF: 0.895

Gnomad AMR exome AF: 0.744

Gnomad ASJ exome AF: 0.421

Gnomad EAS exome AF: 0.997

Gnomad FIN exome AF: 0.418

Gnomad NFE exome AF: 0.402

Gnomad OTH exome AF: 0.503

GnomAD4 exome AF: 0.453 AC: 661843 AN: 1460970 Hom.: 166502 Cov.: 49 AF XY: 0.457 AC XY: 331813 AN XY: 726748

African (AFR) AF: 0.904 AC: 30246 AN: 33462

American (AMR) AF: 0.731 AC: 32677 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.422 AC: 11015 AN: 26110

East Asian (EAS) AF: 0.997 AC: 39538 AN: 39670

South Asian (SAS) AF: 0.680 AC: 58622 AN: 86236

European-Finnish (FIN) AF: 0.414 AC: 22029 AN: 53272

Middle Eastern (MID) AF: 0.529 AC: 3049 AN: 5764

European-Non Finnish (NFE) AF: 0.391 AC: 434758 AN: 1111418

Other (OTH) AF: 0.496 AC: 29909 AN: 60354

GnomAD4 genome AF: 0.592 AC: 90009 AN: 152048 Hom.: 30537 Cov.: 31 AF XY: 0.597 AC XY: 44402 AN XY: 74314

African (AFR) AF: 0.883 AC: 36649 AN: 41514

American (AMR) AF: 0.648 AC: 9886 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.430 AC: 1491 AN: 3470

East Asian (EAS) AF: 0.992 AC: 5146 AN: 5188

South Asian (SAS) AF: 0.697 AC: 3352 AN: 4806

European-Finnish (FIN) AF: 0.413 AC: 4355 AN: 10546

Middle Eastern (MID) AF: 0.538 AC: 157 AN: 292

European-Non Finnish (NFE) AF: 0.402 AC: 27291 AN: 67950

Other (OTH) AF: 0.583 AC: 1231 AN: 2110

Alfa AF: 0.483 Hom.: 32061

Bravo AF: 0.624

TwinsUK AF: 0.385 AC: 1429

ALSPAC AF: 0.392 AC: 1511

ESP6500AA AF: 0.880 AC: 3870

ESP6500EA AF: 0.398 AC: 3422

ExAC AF: 0.563 AC: 68336

Asia WGS AF: 0.857 AC: 2975 AN: 3478

EpiCase AF: 0.407

EpiControl AF: 0.407

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Arthrogryposis, renal dysfunction, and cholestasis 1 (3)
-	-	3	not provided (3)
-	-	3	not specified (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	19
DANN	Benign	0.88
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0000016	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.9	N
PhyloP100		4.3
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	2.7	N
REVEL	Benign	0.24
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0020	B
Vest4		0.076
MPC		0.15
ClinPred		0.0046	T
GERP RS		5.8
Varity_R		0.064
gMVP		0.34
Mutation Taster		=92/8	polymorphism (auto)

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: rs11073964; hg19: chr15-91543761; COSMIC: COSV60980185; COSMIC: COSV60980185;