chr17-42774672-A-G

Position:

• chr17-42774672-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_032353.4(VPS25):​c.226A>G​(p.Ile76Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,613,198 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.010 (25 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (20 hom.)
• Consequence: VPS25 NM_032353.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.70

Genes affected

VPS25 (HGNC:28122): (vacuolar protein sorting 25 homolog) This gene encodes a protein that is a subunit of the endosomal sorting complex required for transport II (ESCRT-II). This protein complex functions in sorting of ubiquitinated membrane proteins during endocytosis. A pseudogene of this gene is present on chromosome 1. [provided by RefSeq, Jul 2013]

VPS25 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001820296).
• BP6: Variant 17-42774672-A-G is Benign according to our data. Variant chr17-42774672-A-G is described in ClinVar as [Benign]. Clinvar id is 791412.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0103 (1562/152132) while in subpopulation AFR AF= 0.0354 (1471/41502). AF 95% confidence interval is 0.0339. There are 25 homozygotes in gnomad4. There are 704 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1562 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VPS25	NM_032353.4	c.226A>G	p.Ile76Val	missense_variant	3/6	ENST00000253794.7	NP_115729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VPS25	ENST00000253794.7	c.226A>G	p.Ile76Val	missense_variant	3/6	1	NM_032353.4	ENSP00000253794.1

Frequencies

GnomAD3 genomes AF: 0.0103 AC: 1562 AN: 152014 Hom.: 26 Cov.: 31

Gnomad AFR AF: 0.0355

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00413

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00767

GnomAD3 exomes AF: 0.00272 AC: 685 AN: 251450 Hom.: 9 AF XY: 0.00205 AC XY: 279 AN XY: 135900

Gnomad AFR exome AF: 0.0364

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.00195

GnomAD4 exome AF: 0.00113 AC: 1645 AN: 1461066 Hom.: 20 Cov.: 30 AF XY: 0.00102 AC XY: 743 AN XY: 726888

Gnomad4 AFR exome AF: 0.0370

Gnomad4 AMR exome AF: 0.00206

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.0000747

Gnomad4 OTH exome AF: 0.00305

GnomAD4 genome AF: 0.0103 AC: 1562 AN: 152132 Hom.: 25 Cov.: 31 AF XY: 0.00947 AC XY: 704 AN XY: 74378

Gnomad4 AFR AF: 0.0354

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00759

Alfa AF: 0.00185 Hom.: 13

Bravo AF: 0.0122

ESP6500AA AF: 0.0374 AC: 165

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00350 AC: 425

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000219

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 13, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	7.7
DANN	Benign	0.87
DEOGEN2	Benign	0.049	T;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.77	T;T
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.97	N;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.070	N;.
REVEL	Benign	0.033
Sift	Benign	0.59	T;.
Sift4G	Benign	0.34	T;T
Polyphen		0.0	B;.
Vest4		0.071
MVP		0.043
MPC		0.51
ClinPred		0.0062	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.034
gMVP		0.079

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs34494804; hg19: chr17-40926690;