19-50790784-G-A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PM5BP4_StrongBS2

The NM_033068.3(ACP4):​c.227G>A​(p.Arg76His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000446 in 1,547,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. R76C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

ACP4
NM_033068.3 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.820

Publications

1 publications found
Variant links:
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]
SMIM47 (HGNC:53452): (small integral membrane protein 47)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

PM5
Other missense variant is known to change same aminoacid residue: Variant chr19-50790783-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 374864.Status of the report is no_assertion_criteria_provided, 0 stars.
BP4
Computational evidence support a benign effect (MetaRNN=0.01895681).
BS2
High AC in GnomAd4 at 33 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ACP4NM_033068.3 linkc.227G>A p.Arg76His missense_variant Exon 3 of 11 ENST00000270593.2 NP_149059.1
LOC105372439XR_936026.3 linkn.435-1069C>T intron_variant Intron 2 of 3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ACP4ENST00000270593.2 linkc.227G>A p.Arg76His missense_variant Exon 3 of 11 1 NM_033068.3 ENSP00000270593.1 Q9BZG2-1
SMIM47ENST00000636757.1 linkc.-59-1069C>T intron_variant Intron 2 of 4 5 ENSP00000489695.1 A0A1B0GTG8

Frequencies

GnomAD3 genomes
AF:
0.000210
AC:
32
AN:
152162
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000529
AC:
8
AN:
151092
AF XY:
0.0000747
show subpopulations
Gnomad AFR exome
AF:
0.000989
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000258
AC:
36
AN:
1395590
Hom.:
0
Cov.:
35
AF XY:
0.0000262
AC XY:
18
AN XY:
688282
show subpopulations
African (AFR)
AF:
0.000698
AC:
22
AN:
31520
American (AMR)
AF:
0.00
AC:
0
AN:
35650
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25142
East Asian (EAS)
AF:
0.00
AC:
0
AN:
35728
South Asian (SAS)
AF:
0.0000632
AC:
5
AN:
79074
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
48012
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4068
European-Non Finnish (NFE)
AF:
0.00000371
AC:
4
AN:
1078618
Other (OTH)
AF:
0.0000865
AC:
5
AN:
57778
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.493
Heterozygous variant carriers
0
2
4
7
9
11
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.000217
AC:
33
AN:
152280
Hom.:
0
Cov.:
32
AF XY:
0.000269
AC XY:
20
AN XY:
74450
show subpopulations
African (AFR)
AF:
0.000746
AC:
31
AN:
41560
American (AMR)
AF:
0.0000653
AC:
1
AN:
15310
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5170
South Asian (SAS)
AF:
0.000207
AC:
1
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10626
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68000
Other (OTH)
AF:
0.00
AC:
0
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.538
Heterozygous variant carriers
0
2
3
5
6
8
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000903
Hom.:
0
Bravo
AF:
0.000276
ESP6500AA
AF:
0.000546
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000754
AC:
4

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
May 30, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.227G>A (p.R76H) alteration is located in exon 3 (coding exon 3) of the ACPT gene. This alteration results from a G to A substitution at nucleotide position 227, causing the arginine (R) at amino acid position 76 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.069
BayesDel_addAF
Benign
-0.52
T
BayesDel_noAF
Benign
-0.59
CADD
Benign
14
DANN
Uncertain
0.99
DEOGEN2
Benign
0.12
T
Eigen
Benign
-0.98
Eigen_PC
Benign
-0.93
FATHMM_MKL
Benign
0.026
N
LIST_S2
Benign
0.69
T
M_CAP
Benign
0.0050
T
MetaRNN
Benign
0.019
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.1
M
PhyloP100
-0.82
PrimateAI
Benign
0.30
T
PROVEAN
Benign
-1.8
N
REVEL
Benign
0.031
Sift
Benign
0.087
T
Sift4G
Benign
0.10
T
Polyphen
0.022
B
Vest4
0.14
MVP
0.055
MPC
0.16
ClinPred
0.068
T
GERP RS
-1.4
PromoterAI
-0.046
Neutral
Varity_R
0.043
gMVP
0.38
Mutation Taster
=61/39
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs201486558; hg19: chr19-51294041; COSMIC: COSV54517025; COSMIC: COSV54517025; API