rs147025508

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001611.5(ACP5):c.814C>T(p.Arg272Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00413 in 1,614,120 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R272H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0033 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0042 ( 21 hom. )

Consequence

ACP5
NM_001611.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:9

Conservation

PhyloP100: 0.612

Variant links:

Genes affected

ACP5 (HGNC:124): (acid phosphatase 5, tartrate resistant) This gene encodes an iron containing glycoprotein which catalyzes the conversion of orthophosphoric monoester to alcohol and orthophosphate. It is the most basic of the acid phosphatases and is the only form not inhibited by L(+)-tartrate. [provided by RefSeq, Aug 2008]

ACP5 links:

ZNF627 (HGNC:30570): (zinc finger protein 627) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF627 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0074237585).

BP6

Variant 19-11575174-G-A is Benign according to our data. Variant chr19-11575174-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198455.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=3, Uncertain_significance=2}. Variant chr19-11575174-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00334 (508/152298) while in subpopulation NFE AF= 0.00563 (383/68026). AF 95% confidence interval is 0.00516. There are 2 homozygotes in gnomad4. There are 230 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACP5	NM_001611.5 linkuse as main transcript	c.814C>T	p.Arg272Cys	missense_variant	5/5	ENST00000648477.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACP5	ENST00000648477.1 linkuse as main transcript	c.814C>T	p.Arg272Cys	missense_variant	5/5		NM_001611.5	P3

Frequencies

GnomAD3 genomes

AF:

0.00334

AC:

508

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000748

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00314

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00283

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00563

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00315

AC:

792

AN:

251074

Hom.:

AF XY:

0.00321

AC XY:

436

AN XY:

135808

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.00376

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00296

Gnomad NFE exome

AF:

0.00484

Gnomad OTH exome

AF:

0.00392

GnomAD4 exome

AF:

0.00421

AC:

6157

AN:

1461822

Hom.:

Cov.:

AF XY:

0.00410

AC XY:

2983

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.000806

Gnomad4 AMR exome

AF:

0.00376

Gnomad4 ASJ exome

AF:

0.00157

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.000197

Gnomad4 FIN exome

AF:

0.00294

Gnomad4 NFE exome

AF:

0.00491

Gnomad4 OTH exome

AF:

0.00411

GnomAD4 genome

AF:

0.00334

AC:

508

AN:

152298

Hom.:

Cov.:

AF XY:

0.00309

AC XY:

230

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.000746

Gnomad4 AMR

AF:

0.00314

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00283

Gnomad4 NFE

AF:

0.00563

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.00413

Hom.:

Bravo

AF:

0.00333

TwinsUK

AF:

0.00728

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00628

AC:

ExAC

AF:

0.00287

AC:

348

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00578

EpiControl

AF:

0.00545

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	ACP5: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 12, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2022	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Spondyloenchondrodysplasia with immune dysregulation

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Nov 23, 2021	ACP5 NM_001111035.2 exon 7 p.Arg272Cys (c.814C>T): This variant has not been reported in the literature but is present in 0.4% (595/126376) of European alleles, including 3 homozygotes, in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/19-11685989-G-A). This variant is present in ClinVar, with several labs classifying this variant as likely benign or benign (Variation ID:198455). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Mar 17, 2017	BS1, BS2, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, was seen in a healthy adult where full penetrance of the disorder is expected at an early age, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 01, 2015	- -

ACP5-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 03, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

D;D;D;D;D

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.84

.;.;.;.;T

M_CAP

Benign

0.070

MetaRNN

Benign

0.0074

T;T;T;T;T

MetaSVM

Benign

-0.67

MutationAssessor

Uncertain

2.1

M;M;M;M;M

MutationTaster

Benign

1.0

N;N;N;N;N

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-2.7

.;D;D;.;D

REVEL

Benign

0.21

Sift

Benign

0.055

.;T;T;.;T

Sift4G

Uncertain

0.059

.;T;T;T;T

Polyphen

0.98

D;D;D;D;D

Vest4

0.34, 0.35, 0.36

MVP

0.78

MPC

0.51

ClinPred

0.017

GERP RS

4.8

Varity_R

0.13

gMVP

0.62

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over