chr19-50790850-G-A

Variant names:

• chr19-50790850-G-A
• rs375408855
• NM_033068.3:c.293G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS2_Supporting

The NM_033068.3(ACP4):​c.293G>A​(p.Arg98Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000879 in 1,547,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. R98W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000087 (0 hom.)
• Consequence: ACP4 NM_033068.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.960
• Publications: 0 publications found

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)

LOC105372439 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04944426).
• BS2: High AC in GnomAd4 at 14 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACP4	NM_033068.3	c.293G>A	p.Arg98Gln	missense_variant	Exon 3 of 11	ENST00000270593.2	NP_149059.1
LOC105372439	XR_936026.3	n.435-1135C>T		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACP4	ENST00000270593.2	c.293G>A	p.Arg98Gln	missense_variant	Exon 3 of 11	1	NM_033068.3	ENSP00000270593.1
SMIM47	ENST00000636757.1	c.-59-1135C>T		intron_variant	Intron 2 of 4	5		ENSP00000489695.1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000601 AC: 9 AN: 149710 AF XY: 0.0000502

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.0000815

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000874 AC: 122 AN: 1395270 Hom.: 0 Cov.: 35 AF XY: 0.0000828 AC XY: 57 AN XY: 688036

African (AFR) AF: 0.00 AC: 0 AN: 31522

American (AMR) AF: 0.0000562 AC: 2 AN: 35600

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25094

East Asian (EAS) AF: 0.00 AC: 0 AN: 35732

South Asian (SAS) AF: 0.00 AC: 0 AN: 78980

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4064

European-Non Finnish (NFE) AF: 0.000109 AC: 118 AN: 1078398

Other (OTH) AF: 0.0000346 AC: 2 AN: 57756

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74422

African (AFR) AF: 0.000217 AC: 9 AN: 41550

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 67978

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000117 Hom.: 0

Bravo AF: 0.000113

ESP6500AA AF: 0.000272 AC: 1

ESP6500EA AF: 0.000144 AC: 1

ExAC AF: 0.0000593 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.293G>A (p.R98Q) 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 293, causing the arginine (R) at amino acid position 98 to be replaced by a glutamine (Q). 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	0.070
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.061	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.96
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.035
Sift	Benign	0.11	T
Sift4G	Benign	0.44	T
Polyphen		0.57	P
Vest4		0.12
MVP		0.072
MPC		0.14
ClinPred		0.029	T
GERP RS		1.2
PromoterAI		-0.014	Neutral
Varity_R		0.035
gMVP		0.32
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs375408855; hg19: chr19-51294107;