Genetic Variant VPS33A:p.Pro595Ser (chr12-122232254-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_022916.6(VPS33A):c.1783C>T(p.Pro595Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,458,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P595T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

VPS33A
NM_022916.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.21

Variant links:

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 links:

ENSG00000256861 (HGNC:):

ENSG00000256861 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15518019).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
VPS33A	NM_022916.6 link	c.1783C>T	p.Pro595Ser	missense_variant	Exon 13 of 13	ENST00000267199.9	NP_075067.2
VPS33A	NM_001351018.2 link	c.1750C>T	p.Pro584Ser	missense_variant	Exon 13 of 13		NP_001337947.1
VPS33A	NM_001351019.2 link	c.1735C>T	p.Pro579Ser	missense_variant	Exon 13 of 13		NP_001337948.1
VPS33A	NM_001351020.2 link	c.1462C>T	p.Pro488Ser	missense_variant	Exon 11 of 11		NP_001337949.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS33A	ENST00000267199.9 link	c.1783C>T	p.Pro595Ser	missense_variant	Exon 13 of 13	1	NM_022916.6	ENSP00000267199.3		Q96AX1
ENSG00000256861	ENST00000535844.1 link	n.1594+72C>T		intron_variant	Intron 12 of 15	2		ENSP00000454454.1		H3BMM5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000403

AC:

AN:

248374

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1458812

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725464

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33376

American (AMR)

AF:

0.00

AC:

AN:

44030

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26054

East Asian (EAS)

AF:

0.00

AC:

AN:

39650

South Asian (SAS)

AF:

0.00

AC:

AN:

85444

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110794

Other (OTH)

AF:

0.00

AC:

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.090

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

T;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.67

T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.16

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;.

PhyloP100

4.2

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.5

N;.

REVEL

Benign

0.065

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

0.0010

B;.

Vest4

0.087

MutPred

0.35

Gain of helix (P = 0.0325);.;

MVP

0.15

MPC

1.2

ClinPred

0.82

GERP RS

4.3

Varity_R

0.29

gMVP

0.94

Mutation Taster

=75/25

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

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