19-11575039-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001611.5(ACP5):c.949A>G(p.Thr317Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T317S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ACP5 NM_001611.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.29

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.123996824).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACP5	NM_001611.5	c.949A>G	p.Thr317Ala	missense_variant	5/5	ENST00000648477.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACP5	ENST00000648477.1	c.949A>G	p.Thr317Ala	missense_variant	5/5		NM_001611.5	P3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152134 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461848 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727226

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152134 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74316

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spondyloenchondrodysplasia with immune dysregulation Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 03, 2022

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 317 of the ACP5 protein (p.Thr317Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ACP5-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	17
Dann	Benign	0.96
DEOGEN2	Benign	0.23	T;T;T;T;T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.61	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.12	T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.1	M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.58	T
Polyphen		0.031	B;B;B;B;B
Vest4		0.19, 0.20, 0.20, 0.21
MutPred		0.53		Loss of phosphorylation at T317 (P = 0.0354);Loss of phosphorylation at T317 (P = 0.0354);Loss of phosphorylation at T317 (P = 0.0354);Loss of phosphorylation at T317 (P = 0.0354);Loss of phosphorylation at T317 (P = 0.0354);
MVP		0.71
MPC		0.30
ClinPred		0.24	T
GERP RS		3.0
Varity_R		0.18
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

Other links and lift over

dbSNP: rs1599630500; hg19: chr19-11685854;