NM_001610.4:c.1136C>G

Variant names:

• chr11-47242725-G-C
• rs564407962
• NM_001610.4:c.1136C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001610.4(ACP2):​c.1136C>G​(p.Thr379Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000657 in 152,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T379I) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: ACP2 NM_001610.4 missense, splice_region
• Scores: Splicing: ADA: 0.01186
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.57
• Publications: 0 publications found

Genes affected

ACP2 (HGNC:123): (acid phosphatase 2, lysosomal) The protein encoded by this gene belongs to the histidine acid phosphatase family, which hydrolyze orthophosphoric monoesters to alcohol and phosphate. This protein is localized to the lysosomal membrane, and is chemically and genetically distinct from the red cell acid phosphatase. Mice lacking this gene showed multiple defects, including bone structure alterations, lysosomal storage defects, and an increased tendency towards seizures. An enzymatically-inactive allele of this gene in mice showed severe growth retardation, hair-follicle abnormalities, and an ataxia-like phenotype. Alternatively spliced transcript variants have been found for this gene. A C-terminally extended isoform is also predicted to be produced by the use of an alternative in-frame translation termination codon via a stop codon readthrough mechanism. [provided by RefSeq, Oct 2017]

ACP2 Gene-Disease associations (from GenCC):

• lysosomal acid phosphatase deficiency

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17140919).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001610.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACP2	NM_001610.4	MANE Select	c.1136C>G	p.Thr379Arg	missense splice_region	Exon 10 of 11	NP_001601.1	P11117-1
	ACP2	NM_001357016.2		c.1136C>G	p.Thr379Arg	missense splice_region	Exon 10 of 11	NP_001343945.1	A0A5F9ZHR7
	ACP2	NM_001302489.2		c.1052C>G	p.Thr351Arg	missense splice_region	Exon 10 of 11	NP_001289418.1	E9PQY3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACP2	ENST00000672073.1	MANE Select	c.1136C>G	p.Thr379Arg	missense splice_region	Exon 10 of 11	ENSP00000500291.1	P11117-1
	ACP2	ENST00000256997.9	TSL:1	c.1136C>G	p.Thr379Arg	missense splice_region	Exon 10 of 11	ENSP00000256997.3	P11117-1
	ACP2	ENST00000672636.2		c.1136C>G	p.Thr379Arg	missense splice_region	Exon 10 of 11	ENSP00000500571.2	A0A5F9ZHR7

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152232 Hom.: 0 Cov.: 33

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: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152232 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74374

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.0063	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.022
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0053	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.6
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.16
Sift	Benign	0.54	T
Sift4G	Benign	0.53	T
Polyphen		0.014	B
Vest4		0.47
MutPred		0.41		Gain of sheet (P = 0.0344)
MVP		0.23
MPC		0.41
ClinPred		0.45	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.70
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.012
dbscSNV1_RF	Benign	0.14
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: rs564407962; hg19: chr11-47264276;