Genetic Variant VPS41:c.2405-5G>C (chr7-38726993-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014396.4(VPS41):c.2405-5G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000718 in 1,392,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

VPS41
NM_014396.4 splice_region, intron

Scores

Splicing: ADA: 0.00002294

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.81

Publications

0 publications found

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]

VPS41 Gene-Disease associations (from GenCC):

spinocerebellar ataxia, autosomal recessive 29
Inheritance: Unknown, AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
autosomal recessive cerebellar ataxia-saccadic intrusion syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

VPS41 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014396.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VPS41	NM_014396.4	MANE Select	c.2405-5G>C		splice_region intron	N/A	NP_055211.2	P49754-1
	VPS41	NM_080631.4		c.2330-5G>C		splice_region intron	N/A	NP_542198.2	P49754-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
VPS41	ENST00000310301.9	TSL:1 MANE Select	c.2405-5G>C	splice_region intron	N/A	ENSP00000309457.4	P49754-1
VPS41	ENST00000448833.5	TSL:1	n.*90-5G>C	splice_region intron	N/A	ENSP00000391980.1	H7BZX6
VPS41	ENST00000951460.1		c.2501-5G>C	splice_region intron	N/A	ENSP00000621519.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.18e-7

AC:

AN:

1392566

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

691434

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30040

American (AMR)

AF:

0.00

AC:

AN:

35144

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23956

East Asian (EAS)

AF:

0.00

AC:

AN:

35418

South Asian (SAS)

AF:

0.00

AC:

AN:

76570

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52148

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5358

European-Non Finnish (NFE)

AF:

9.29e-7

AC:

AN:

1076862

Other (OTH)

AF:

0.00

AC:

AN:

57070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.10

(source)

DANN

Benign

0.49

PhyloP100

-1.8

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000023

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over