rs140376049

chr17-532865-T-C

Variant summary

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

The NM_001128159.3(VPS53):c.2062A>G(p.Ile688Val) variant causes a missense change. The variant allele was found at a frequency of 0.00184 in 1,614,096 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (17 hom.)
• Consequence: VPS53 NM_001128159.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:5
• Conservation: PhyloP100: 3.90

Genes affected

VPS53 (HGNC:25608): (VPS53 subunit of GARP complex) Involved in endocytic recycling and retrograde transport, endosome to Golgi. Acts upstream of or within lysosomal transport. Located in several cellular components, including Golgi apparatus; perinuclear region of cytoplasm; and recycling endosome. Part of EARP complex and GARP complex. Implicated in pontocerebellar hypoplasia type 2E. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009616137).
• BP6: Variant 17-532865-T-C is Benign according to our data. Variant chr17-532865-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 376850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00183 (278/152314) while in subpopulation SAS AF= 0.0137 (66/4828). AF 95% confidence interval is 0.011. There are 3 homozygotes in gnomad4. There are 150 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VPS53	NM_001128159.3	c.2062A>G	p.Ile688Val	missense_variant	19/22	ENST00000437048.7
LOC124903890	XR_007065570.1	n.694-7524T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VPS53	ENST00000437048.7	c.2062A>G	p.Ile688Val	missense_variant	19/22	1	NM_001128159.3	P1
	ENST00000570974.1	n.291-7524T>C		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.00183 AC: 278 AN: 152196 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00674

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00338 AC: 842 AN: 248750 Hom.: 8 AF XY: 0.00378 AC XY: 509 AN XY: 134660

Gnomad AFR exome AF: 0.000432

Gnomad AMR exome AF: 0.00298

Gnomad ASJ exome AF: 0.00338

Gnomad EAS exome AF: 0.00870

Gnomad SAS exome AF: 0.0118

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00134

Gnomad OTH exome AF: 0.00425

GnomAD4 exome AF: 0.00184 AC: 2686 AN: 1461782 Hom.: 17 Cov.: 31 AF XY: 0.00212 AC XY: 1543 AN XY: 727164

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00293

Gnomad4 ASJ exome AF: 0.00390

Gnomad4 EAS exome AF: 0.00501

Gnomad4 SAS exome AF: 0.0108

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.000975

Gnomad4 OTH exome AF: 0.00265

GnomAD4 genome AF: 0.00183 AC: 278 AN: 152314 Hom.: 3 Cov.: 32 AF XY: 0.00201 AC XY: 150 AN XY: 74480

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.00518

Gnomad4 EAS AF: 0.00675

Gnomad4 SAS AF: 0.0137

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00122

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00188 Hom.: 1

Bravo AF: 0.00186

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00347 AC: 421

Asia WGS AF: 0.00837 AC: 29 AN: 3478

EpiCase AF: 0.00158

EpiControl AF: 0.00219

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 20, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	VPS53: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2018	- -

Microcephaly Uncertain:1

Uncertain significance, no assertion criteria provided

research

Department of Pediatrics, Samsung Medical Center, Samsung Medical Center

-

- -

Pontocerebellar hypoplasia type 2E Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	19
Dann	Uncertain	0.99
Eigen	Benign	-0.18
Eigen_PC	Benign	0.014
FATHMM_MKL	Uncertain	0.96	D
MetaRNN	Benign	0.0096	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;.;L;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.37	N;N;.;N
REVEL	Benign	0.036
Sift	Benign	0.44	T;T;.;T
Sift4G	Benign	0.53	T;T;T;T
Polyphen		0.0040	B;B;B;B
Vest4		0.34
MVP		0.23
MPC		0.29
ClinPred		0.0061	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.091
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs140376049; hg19: chr17-436105; COSMIC: COSV52131961; COSMIC: COSV52131961;