7-38726257-T-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.2554A>G(p.Met852Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000033 in 1,608,438 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M852T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000033 (1 hom.)
• Consequence: VPS41 NM_014396.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.41

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=0.042853773).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS41	NM_014396.4	c.2554A>G	p.Met852Val	missense_variant	29/29	ENST00000310301.9
VPS41	NM_080631.4	c.2479A>G	p.Met827Val	missense_variant	28/28
VPS41	XM_017011988.2	c.1399A>G	p.Met467Val	missense_variant	16/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS41	ENST00000310301.9	c.2554A>G	p.Met852Val	missense_variant	29/29	1	NM_014396.4	P1
VPS41	ENST00000448833.5	c.*239A>G		3_prime_UTR_variant, NMD_transcript_variant	8/8	1
VPS41	ENST00000395969.6	c.2479A>G	p.Met827Val	missense_variant	28/28	5
VPS41	ENST00000490924.1	n.348A>G		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151802 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000847 AC: 21 AN: 248042 Hom.: 0 AF XY: 0.0000968 AC XY: 13 AN XY: 134240

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000816

Gnomad SAS exome AF: 0.0000982

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000900

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.0000330 AC: 48 AN: 1456518 Hom.: 1 Cov.: 29 AF XY: 0.0000331 AC XY: 24 AN XY: 724780

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000504

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.000266

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 151920 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74230

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000770

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000576 AC: 7

Asia WGS AF: 0.00404 AC: 14 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

Oct 10, 2023

The c.2554A>G (p.M852V) alteration is located in exon 29 (coding exon 29) of the VPS41 gene. This alteration results from a A to G substitution at nucleotide position 2554, causing the methionine (M) at amino acid position 852 to be replaced by a valine (V). 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	0.11
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	21
Dann	Benign	0.96
DEOGEN2	Benign	0.013	T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.12
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.043	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.19	N;N
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.39	T;T
Polyphen		0.0040	B;.
Vest4		0.52
MutPred		0.21		Gain of methylation at K853 (P = 0.0776);.;
MVP		0.22
MPC		0.30
ClinPred		0.19	T
GERP RS		1.6
Varity_R		0.69
gMVP		0.71

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs377433367; hg19: chr7-38765857;