7-38728574-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS1_ModeratePM2PP3_ModeratePP5

The NM_014396.4(VPS41):​c.2372G>T​(p.Cys791Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C791R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

VPS41
NM_014396.4 missense

Scores

14
4
1

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 5.83
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PS1
Transcript NM_014396.4 (VPS41) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.928
PP5
Variant 7-38728574-C-A is Pathogenic according to our data. Variant chr7-38728574-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1175719.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
VPS41NM_014396.4 linkc.2372G>T p.Cys791Phe missense_variant Exon 27 of 29 ENST00000310301.9 NP_055211.2 P49754-1
VPS41NM_080631.4 linkc.2297G>T p.Cys766Phe missense_variant Exon 26 of 28 NP_542198.2 P49754-3
VPS41XM_017011988.2 linkc.1217G>T p.Cys406Phe missense_variant Exon 14 of 16 XP_016867477.1
VPS41XR_007060008.1 linkn.2389G>T non_coding_transcript_exon_variant Exon 27 of 29

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
VPS41ENST00000310301.9 linkc.2372G>T p.Cys791Phe missense_variant Exon 27 of 29 1 NM_014396.4 ENSP00000309457.4 P49754-1
VPS41ENST00000448833.5 linkn.413G>T non_coding_transcript_exon_variant Exon 5 of 8 1 ENSP00000391980.1 H7BZX6
VPS41ENST00000395969.6 linkc.2297G>T p.Cys766Phe missense_variant Exon 26 of 28 5 ENSP00000379297.2 P49754-3
VPS41ENST00000482217.1 linkn.831G>T non_coding_transcript_exon_variant Exon 5 of 7 5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Spinocerebellar ataxia, autosomal recessive 29 Pathogenic:1
Jul 06, 2021
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.57
CADD
Pathogenic
29
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.60
D;.
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;D
M_CAP
Pathogenic
0.61
D
MetaRNN
Pathogenic
0.93
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.1
M;.
PrimateAI
Uncertain
0.72
T
PROVEAN
Pathogenic
-9.1
D;D
REVEL
Pathogenic
0.85
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;.
Vest4
0.95
MutPred
0.63
Loss of catalytic residue at S793 (P = 0.025);.;
MVP
0.96
MPC
1.2
ClinPred
1.0
D
GERP RS
5.8
Varity_R
0.96
gMVP
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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.

Other links and lift over

hg19: chr7-38768174; API