20-2860454-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_022575.4(VPS16):c.375G>A(p.Val125=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00169 in 1,614,094 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (6 hom.)
• Consequence: VPS16 NM_022575.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0300

Genes affected

VPS16 (HGNC:14584): (VPS16 core subunit of CORVET and HOPS complexes) 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 homolog of yeast class C Vps16 protein. The mammalian class C Vps proteins are predominantly associated with late endosomes/lysosomes, and like their yeast counterparts, may mediate vesicle trafficking steps in the endosome/lysosome pathway. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2009]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 20-2860454-G-A is Benign according to our data. Variant chr20-2860454-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2652157.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.03 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS16	NM_022575.4	c.375G>A	p.Val125=	synonymous_variant	5/24	ENST00000380445.8
VPS16	NM_080413.3	c.375G>A	p.Val125=	synonymous_variant	5/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS16	ENST00000380445.8	c.375G>A	p.Val125=	synonymous_variant	5/24	1	NM_022575.4	P1
VPS16	ENST00000380469.7	c.375G>A	p.Val125=	synonymous_variant	5/20	2
VPS16	ENST00000453689.5	c.21G>A	p.Val7=	synonymous_variant	3/10	3
VPS16	ENST00000417508.1	c.21G>A	p.Val7=	synonymous_variant	3/9	5

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 211 AN: 152114 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00234

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00134 AC: 338 AN: 251444 Hom.: 0 AF XY: 0.00133 AC XY: 181 AN XY: 135892

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00105

Gnomad FIN exome AF: 0.00166

Gnomad NFE exome AF: 0.00209

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00172 AC: 2518 AN: 1461862 Hom.: 6 Cov.: 33 AF XY: 0.00170 AC XY: 1239 AN XY: 727236

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00110

Gnomad4 FIN exome AF: 0.00198

Gnomad4 NFE exome AF: 0.00196

Gnomad4 OTH exome AF: 0.00179

GnomAD4 genome AF: 0.00139 AC: 211 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.00142 AC XY: 106 AN XY: 74422

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.00234

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00206 Hom.: 0

Bravo AF: 0.00119

EpiCase AF: 0.00191

EpiControl AF: 0.00172

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

VPS16: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	0.23
Dann	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs144621348; hg19: chr20-2841100;