7-38726982-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014396.4(VPS41):c.2411C>G(p.Ala804Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000053 in 1,566,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: VPS41 NM_014396.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.37

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.01783982).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS41	NM_014396.4	c.2411C>G	p.Ala804Gly	missense_variant	28/29	ENST00000310301.9
VPS41	NM_080631.4	c.2336C>G	p.Ala779Gly	missense_variant	27/28
VPS41	XM_017011988.2	c.1256C>G	p.Ala419Gly	missense_variant	15/16
VPS41	XR_007060008.1	n.2522C>G		non_coding_transcript_exon_variant	29/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS41	ENST00000310301.9	c.2411C>G	p.Ala804Gly	missense_variant	28/29	1	NM_014396.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152232 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000139 AC: 30 AN: 215482 Hom.: 0 AF XY: 0.000136 AC XY: 16 AN XY: 117490

Gnomad AFR exome AF: 0.000293

Gnomad AMR exome AF: 0.000111

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00149

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000403

GnomAD4 exome AF: 0.0000495 AC: 70 AN: 1414224 Hom.: 0 Cov.: 30 AF XY: 0.0000455 AC XY: 32 AN XY: 702892

Gnomad4 AFR exome AF: 0.000225

Gnomad4 AMR exome AF: 0.000103

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000416

Gnomad4 SAS exome AF: 0.0000125

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.20e-7

Gnomad4 OTH exome AF: 0.000722

GnomAD4 genome AF: 0.0000853 AC: 13 AN: 152350 Hom.: 0 Cov.: 33 AF XY: 0.0000805 AC XY: 6 AN XY: 74494

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.000185

ExAC AF: 0.000165 AC: 20

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 17, 2023

The c.2411C>G (p.A804G) alteration is located in exon 28 (coding exon 28) of the VPS41 gene. This alteration results from a C to G substitution at nucleotide position 2411, causing the alanine (A) at amino acid position 804 to be replaced by a glycine (G). 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	0.077
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.55
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.011	T;.
Eigen	Benign	-0.17
Eigen_PC	Benign	0.048
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.018	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.90	L;.
MutationTaster	Benign	0.72	D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.46	N;N
REVEL	Benign	0.079
Sift	Benign	0.34	T;T
Sift4G	Benign	0.38	T;T
Polyphen		0.0010	B;.
Vest4		0.13
MutPred		0.39		Loss of stability (P = 0.0413);.;
MVP		0.72
MPC		0.29
ClinPred		0.016	T
GERP RS		4.4
Varity_R		0.085
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs376616603; hg19: chr7-38766582;