dbSNP rs149584623: VPS41:p.Arg815Pro (chr7-38726949-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_014396.4(VPS41):c.2444G>C(p.Arg815Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,438,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R815Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

VPS41
NM_014396.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.57

Variant links:

Genes affected

VPS41 (HGNC:12713): (VPS41 subunit of HOPS complex) 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 encodes the human ortholog of yeast Vps41 protein which is also conserved in Drosophila, tomato, and Arabidopsis. Expression studies in yeast and human indicate that this protein may be involved in the formation and fusion of transport vesicles from the Golgi. Several transcript variants encoding different isoforms have been described for this gene, however, the full-length nature of not all is known. [provided by RefSeq, Jul 2008]

VPS41 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.833

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS41	NM_014396.4 link	c.2444G>C	p.Arg815Pro	missense_variant	Exon 28 of 29	ENST00000310301.9	NP_055211.2	P49754-1
VPS41	NM_080631.4 link	c.2369G>C	p.Arg790Pro	missense_variant	Exon 27 of 28		NP_542198.2	P49754-3
VPS41	XM_017011988.2 link	c.1289G>C	p.Arg430Pro	missense_variant	Exon 15 of 16		XP_016867477.1
VPS41	XR_007060008.1 link	n.2555G>C		non_coding_transcript_exon_variant	Exon 29 of 29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS41	ENST00000310301.9 link	c.2444G>C	p.Arg815Pro	missense_variant	Exon 28 of 29	1	NM_014396.4	ENSP00000309457.4		P49754-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1438482

Hom.:

Cov.:

AF XY:

0.00000280

AC XY:

AN XY:

715326

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000120

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.09e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

T;.

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.83

D;D

MetaSVM

Uncertain

-0.19

MutationAssessor

Uncertain

2.6

M;.

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.9

D;D

REVEL

Uncertain

0.58

Sift

Benign

0.063

T;T

Sift4G

Uncertain

0.022

D;D

Polyphen

1.0

D;.

Vest4

0.92

MutPred

0.49

Gain of disorder (P = 0.0546);.;

MVP

0.88

MPC

1.1

ClinPred

0.99

GERP RS

5.5

Varity_R

0.73

gMVP

0.90

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over