chr19-11575197-ATGAAATTCCCAGCCCCACT-A

Variant names:

• chr19-11575197-ATGAAATTCCCAGCCCCACT-A
• rs878853218
• NM_001611.5:c.772_790delAGTGGGGCTGGGAATTTCA

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001611.5(ACP5):​c.772_790delAGTGGGGCTGGGAATTTCA​(p.Ser258TrpfsTer39) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ACP5 NM_001611.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.51

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]

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]

LOC124904638 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.211 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-11575197-ATGAAATTCCCAGCCCCACT-A is Pathogenic according to our data. Variant chr19-11575197-ATGAAATTCCCAGCCCCACT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 225659.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-11575197-ATGAAATTCCCAGCCCCACT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACP5	NM_001611.5	c.772_790delAGTGGGGCTGGGAATTTCA	p.Ser258TrpfsTer39	frameshift_variant	Exon 5 of 5	ENST00000648477.1	NP_001602.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACP5	ENST00000648477.1	c.772_790delAGTGGGGCTGGGAATTTCA	p.Ser258TrpfsTer39	frameshift_variant	Exon 5 of 5		NM_001611.5	ENSP00000496973.1

Frequencies

GnomAD3 genomes Cov.: 31

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

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spondyloenchondrodysplasia with immune dysregulation Pathogenic:3

Jul 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ser258Trpfs*39) in the ACP5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 68 amino acid(s) of the ACP5 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with spondyloenchondrodysplasia with immune dysregulation (PMID: 21217755). ClinVar contains an entry for this variant (Variation ID: 225659). This variant disrupts a region of the ACP5 protein in which other variant(s) (p.Ser267*) have been determined to be pathogenic (PMID: 21217752). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Sep 01, 2022

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift variant is predicted to result in a loss or disruption of normal protein function through protein truncation. The predicted truncated protein may be shortened by more than 10%. 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: 21217755 , 26789720). The variant has been reported to be associated with ACP5-related disorder (ClinVar ID: VCV000225659). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Feb 01, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs878853218; hg19: chr19-11686012;