rs6132976

Variant names:

• chr20-2844405-G-A
• rs6132976
• NM_022575.4:c.53+3578G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_022575.4(VPS16):​c.53+3578G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0391 in 152,190 control chromosomes in the GnomAD database, including 231 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.039 (231 hom., cov: 32)
• Consequence: VPS16 NM_022575.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.473
• Publications: 2 publications found

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]

VPS16 Gene-Disease associations (from GenCC):

• dystonia 30

  Inheritance: AR, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• isolated dystonia

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VPS16	NM_022575.4	c.53+3578G>A		intron_variant	Intron 1 of 23	ENST00000380445.8	NP_072097.2
VPS16	NM_080413.3	c.53+3578G>A		intron_variant	Intron 1 of 19		NP_536338.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VPS16	ENST00000380445.8	c.53+3578G>A		intron_variant	Intron 1 of 23	1	NM_022575.4	ENSP00000369810.3
VPS16	ENST00000380469.7	c.53+3578G>A		intron_variant	Intron 1 of 19	2		ENSP00000369836.3
VPS16	ENST00000453689.5	c.-75+3578G>A		intron_variant	Intron 1 of 9	3		ENSP00000417031.1
VPS16	ENST00000417508.1	c.-75+3578G>A		intron_variant	Intron 1 of 8	5		ENSP00000409840.1

Frequencies

GnomAD3 genomes AF: 0.0389 AC: 5921 AN: 152074 Hom.: 221 Cov.: 32

Gnomad AFR AF: 0.0603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.0864

Gnomad SAS AF: 0.0480

Gnomad FIN AF: 0.0219

Gnomad MID AF: 0.0382

Gnomad NFE AF: 0.0108

Gnomad OTH AF: 0.0430

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0391 AC: 5948 AN: 152190 Hom.: 231 Cov.: 32 AF XY: 0.0409 AC XY: 3046 AN XY: 74406

African (AFR) AF: 0.0606 AC: 2514 AN: 41516

American (AMR) AF: 0.105 AC: 1601 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0271 AC: 94 AN: 3468

East Asian (EAS) AF: 0.0860 AC: 445 AN: 5174

South Asian (SAS) AF: 0.0466 AC: 225 AN: 4826

European-Finnish (FIN) AF: 0.0219 AC: 232 AN: 10596

Middle Eastern (MID) AF: 0.0377 AC: 11 AN: 292

European-Non Finnish (NFE) AF: 0.0108 AC: 736 AN: 68016

Other (OTH) AF: 0.0426 AC: 90 AN: 2114

Alfa AF: 0.0427 Hom.: 187

Bravo AF: 0.0474

Asia WGS AF: 0.0820 AC: 284 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.7
DANN	Benign	0.77
PhyloP100		-0.47
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6132976; hg19: chr20-2825051;