rs1085307111

Positions:

• chr19-50793784-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_033068.3(ACP4):​c.746C>T​(p.Pro249Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACP4 NM_033068.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.27

Genes affected

ACP4 (HGNC:14376): (acid phosphatase 4) Acid phosphatases are enzymes capable of hydrolyzing orthophosphoric acid esters in an acid medium. This gene is up-regulated by androgens and is down-regulated by estrogens in the prostate cancer cell line. This gene exhibits a lower level of expression in testicular cancer tissues than in normal tissues. The protein encoded by this gene has structural similarity to prostatic and lysosomal acid phosphatases. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-50793784-C-T is Pathogenic according to our data. Variant chr19-50793784-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 375694.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.28686902). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACP4	NM_033068.3	c.746C>T	p.Pro249Leu	missense_variant	7/11	ENST00000270593.2	NP_149059.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACP4	ENST00000270593.2	c.746C>T	p.Pro249Leu	missense_variant	7/11	1	NM_033068.3	ENSP00000270593.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Amelogenesis imperfecta, type 1J Pathogenic:1

Pathogenic, no assertion criteria provided

research

Leeds Amelogenesis Imperfecta Research Group, University of Leeds

Oct 28, 2016

The variant is predicted to be pathogenic / deleterious by a number of different algorithms, including polyphen-2, CADD, and SIFT. The affected residue P249 (NP_149059.1) is conserved in mammalian orthologues but not in paralogous sequences. The residue lies within in the extracellular domain (residues 29-390) of ACPT. P249 is predicted to form a twist between two alpha helices (Swissmodel Q9BZG2), and substitution of a rigid proline at position 249 with the much larger leucine (BLOSUM62 score -3) is likely to influence the structure of the active site by disrupting that twist.The variant is absent from publicly available databases of variation including dbSNP146, Exome Variant Server and ExAC v0.3. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.066	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.0	L
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.23
Sift	Uncertain	0.029	D
Sift4G	Benign	0.61	T
Polyphen		0.98	D
Vest4		0.36
MutPred		0.56		Loss of catalytic residue at P248 (P = 0.0121);
MVP		0.27
MPC		0.56
ClinPred		0.92	D
GERP RS		4.6
Varity_R		0.058
gMVP		0.65

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: rs1085307111; hg19: chr19-51297041;