rs781050795

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_001611.5(ACP5):c.325G>A(p.Gly109Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000273 in 1,613,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G109G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

ACP5
NM_001611.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 7.10

Publications

9 publications found

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:

LOC124904638 (HGNC:):

LOC124904638 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 19-11576780-C-T is Pathogenic according to our data. Variant chr19-11576780-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 29833.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACP5	NM_001611.5 link	c.325G>A	p.Gly109Arg	missense_variant	Exon 3 of 5	ENST00000648477.1	NP_001602.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACP5	ENST00000648477.1 link	c.325G>A	p.Gly109Arg	missense_variant	Exon 3 of 5		NM_001611.5	ENSP00000496973.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000318

AC:

AN:

251488

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000439

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000274

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

727242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000324

AC:

AN:

1112010

Other (OTH)

AF:

0.0000662

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152032

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74234

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41400

American (AMR)

AF:

0.0000657

AC:

AN:

15232

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000815

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Spondyloenchondrodysplasia with immune dysregulation

Pathogenic:5

Feb 01, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Dec 18, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ACP5 c.325G>A (p.Gly109Arg) results in a non-conservative amino acid change located in the Calcineurin-like phosphoesterase domain, ApaH type domain (IPR004843) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251488 control chromosomes. c.325G>A has been reported in multiple individuals affected with Spondyloenchondrodysplasia with immune dysregulation (e.g. Lausch_2011, Gernez_2023, Labcorp (formerly Invitae)). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 21217752, 38347954). ClinVar contains an entry for this variant (Variation ID: 29833). Based on the evidence outlined above, the variant was classified as pathogenic. -

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 109 of the ACP5 protein (p.Gly109Arg). This variant is present in population databases (rs781050795, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of spondyloenchondrodysplasia with immune dysregulation (PMID: 21217752, 26951490; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 29833). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ACP5 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Aug 26, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PS4 strong, PM2 supporting, PM3 very strong, PP3 supporting -

Sep 01, 2022

3billion

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.90; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000029833). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 21217752). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Inborn genetic diseases

Pathogenic:1

May 15, 2017

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ACP5-related disorder

Pathogenic:1

Jan 17, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ACP5 c.325G>A variant is predicted to result in the amino acid substitution p.Gly109Arg. This variant has been reported along with another variant in ACP5 or in the homozygous state in individuals with spondyloenchondrodysplasia (SPENCD) (Lausch et al. 2011. PubMed ID: 21217752; Briggs et al. 2016. PubMed ID: 26951490). This variant is reported in 0.010% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-11687595-C-T) and is interpreted as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/29833/). This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

D;D;D;D;D;D

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

1.0

.;.;.;.;D;D

M_CAP

Pathogenic

0.44

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

4.5

H;H;H;H;H;.

PhyloP100

7.1

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-8.0

.;D;D;.;D;.

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

.;D;D;.;D;.

Sift4G

Pathogenic

0.0

.;D;D;D;D;.

Polyphen

1.0

D;D;D;D;D;.

Vest4

0.99, 0.99

MutPred

0.98

Gain of MoRF binding (P = 0.0532);Gain of MoRF binding (P = 0.0532);Gain of MoRF binding (P = 0.0532);Gain of MoRF binding (P = 0.0532);Gain of MoRF binding (P = 0.0532);Gain of MoRF binding (P = 0.0532);

MVP

0.97

MPC

1.1

ClinPred

1.0

GERP RS

3.8

Varity_R

0.99

gMVP

1.0

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over