7-38726932-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014396.4(VPS41):​c.2461G>A​(p.Glu821Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

VPS41
NM_014396.4 missense

Scores

2
7
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
VPS41NM_014396.4 linkc.2461G>A p.Glu821Lys missense_variant Exon 28 of 29 ENST00000310301.9 NP_055211.2 P49754-1
VPS41NM_080631.4 linkc.2386G>A p.Glu796Lys missense_variant Exon 27 of 28 NP_542198.2 P49754-3
VPS41XM_017011988.2 linkc.1306G>A p.Glu436Lys missense_variant Exon 15 of 16 XP_016867477.1
VPS41XR_007060008.1 linkn.2572G>A non_coding_transcript_exon_variant Exon 29 of 29

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
VPS41ENST00000310301.9 linkc.2461G>A p.Glu821Lys missense_variant Exon 28 of 29 1 NM_014396.4 ENSP00000309457.4 P49754-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Nov 26, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.2461G>A (p.E821K) alteration is located in exon 28 (coding exon 28) of the VPS41 gene. This alteration results from a G to A substitution at nucleotide position 2461, causing the glutamic acid (E) at amino acid position 821 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Uncertain
-0.030
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.035
T;.
Eigen
Benign
0.15
Eigen_PC
Uncertain
0.32
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Benign
0.024
T
MetaRNN
Uncertain
0.58
D;D
MetaSVM
Benign
-0.89
T
MutationAssessor
Benign
1.8
L;.
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
-1.7
N;N
REVEL
Benign
0.24
Sift
Benign
0.27
T;T
Sift4G
Uncertain
0.035
D;D
Polyphen
0.65
P;.
Vest4
0.77
MutPred
0.28
Gain of methylation at E821 (P = 8e-04);.;
MVP
0.69
MPC
0.49
ClinPred
0.90
D
GERP RS
5.5
Varity_R
0.21
gMVP
0.56

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.

Other links and lift over

hg19: chr7-38766532; API