7-38728574-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PS1_Moderate PM2 PP3_Moderate PP5

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 same amino acid change has been previously reported as Likely pathogenicin 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
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.83

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_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/exons	MANE	UniProt
VPS41	NM_014396.4	c.2372G>T	p.Cys791Phe	missense_variant	27/29	ENST00000310301.9
VPS41	NM_080631.4	c.2297G>T	p.Cys766Phe	missense_variant	26/28
VPS41	XM_017011988.2	c.1217G>T	p.Cys406Phe	missense_variant	14/16
VPS41	XR_007060008.1	n.2389G>T		non_coding_transcript_exon_variant	27/29

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS41	ENST00000310301.9	c.2372G>T	p.Cys791Phe	missense_variant	27/29	1	NM_014396.4	P1
VPS41	ENST00000448833.5	c.416G>T	p.Cys139Phe	missense_variant, NMD_transcript_variant	5/8	1
VPS41	ENST00000395969.6	c.2297G>T	p.Cys766Phe	missense_variant	26/28	5
VPS41	ENST00000482217.1	n.831G>T		non_coding_transcript_exon_variant	5/7	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

Submissions by phenotype

Spinocerebellar ataxia, autosomal recessive 29 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 06, 2021

- -

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;.
MutationTaster	Benign	1.0	D;D
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;