7-38726993-C-A

Variant summary

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

The NM_014396.4(VPS41):c.2405-5G>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,544,746 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000099 (0 hom.)
• Consequence: VPS41 NM_014396.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002029
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.81

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 (BayesDel_noAF=-0.8).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS41	NM_014396.4	c.2405-5G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000310301.9
VPS41	NM_080631.4	c.2330-5G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
VPS41	XM_017011988.2	c.1250-5G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
VPS41	XR_007060008.1	n.2516-5G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS41	ENST00000310301.9	c.2405-5G>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_014396.4	P1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152066 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000178 AC: 36 AN: 202114 Hom.: 0 AF XY: 0.000199 AC XY: 22 AN XY: 110594

Gnomad AFR exome AF: 0.0000765

Gnomad AMR exome AF: 0.000418

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000863

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000178

Gnomad OTH exome AF: 0.000431

GnomAD4 exome AF: 0.0000991 AC: 138 AN: 1392562 Hom.: 0 Cov.: 30 AF XY: 0.0000998 AC XY: 69 AN XY: 691430

Gnomad4 AFR exome AF: 0.000300

Gnomad4 AMR exome AF: 0.000398

Gnomad4 ASJ exome AF: 0.000167

Gnomad4 EAS exome AF: 0.0000282

Gnomad4 SAS exome AF: 0.0000522

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000752

Gnomad4 OTH exome AF: 0.000280

GnomAD4 genome AF: 0.000145 AC: 22 AN: 152184 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74392

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000144 Hom.: 0

Bravo AF: 0.000208

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

May 11, 2022

The c.2405-5G>T intronic alteration consists of a G to T substitution 5 nucleotides before coding exon 28 in the VPS41 gene. 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
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.10
Dann	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000020
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

LitVar

Other links and lift over

dbSNP: rs144271652; hg19: chr7-38766593;