NM_001632.5:c.74C>T

Variant names:

• chr2-232378876-C-T
• rs1130335
• NM_001632.5:c.74C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001632.5(ALPP):​c.74C>T​(p.Pro25Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.081 in 1,613,864 control chromosomes in the GnomAD database, including 6,187 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.070 (485 hom., cov: 32)
  • Exomes 𝑓: 0.082 (5702 hom.)
• Consequence: ALPP NM_001632.5 missense, splice_region
• Scores: Splicing: ADA: 0.8676
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.71
• Publications: 15 publications found

Genes affected

ALPP (HGNC:439): (alkaline phosphatase, placental) The protein encoded by this gene is an alkaline phosphatase, a metalloenzyme that catalyzes the hydrolysis of phosphoric acid monoesters. It belongs to a multigene family composed of four alkaline phosphatase isoenzymes. The enzyme functions as a homodimer and has a catalytic site containing one magnesium and two zinc ions, which are required for its enzymatic function. One of the main sources of this enzyme is the liver, and thus, it's one of several indicators of liver injury in different clinical conditions. In pregnant women, this protein is primarily expressed in placental and endometrial tissue, however, strong ectopic expression has been detected in ovarian adenocarcinoma, serous cystadenocarcinoma, and other ovarian cancer cells. [provided by RefSeq, Aug 2020]

ECEL1P2 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017961562).
• BP6: Variant 2-232378876-C-T is Benign according to our data. Variant chr2-232378876-C-T is described in ClinVar as Benign. ClinVar VariationId is 13661.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001632.5. 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
	ALPP	NM_001632.5	MANE Select	c.74C>T	p.Pro25Leu	missense splice_region	Exon 1 of 11	NP_001623.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALPP	ENST00000392027.3	TSL:1 MANE Select	c.74C>T	p.Pro25Leu	missense splice_region	Exon 1 of 11	ENSP00000375881.2
	ALPP	ENST00000474529.1	TSL:2	n.153C>T		splice_region non_coding_transcript_exon	Exon 1 of 4
	ECEL1P2	ENST00000715297.1		n.812+69G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0702 AC: 10670 AN: 151936 Hom.: 485 Cov.: 32

Gnomad AFR AF: 0.0385

Gnomad AMI AF: 0.0593

Gnomad AMR AF: 0.0564

Gnomad ASJ AF: 0.0525

Gnomad EAS AF: 0.224

Gnomad SAS AF: 0.0720

Gnomad FIN AF: 0.0587

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0835

Gnomad OTH AF: 0.0740

GnomAD2 exomes AF: 0.0801 AC: 20113 AN: 251184 AF XY: 0.0802

Gnomad AFR exome AF: 0.0393

Gnomad AMR exome AF: 0.0377

Gnomad ASJ exome AF: 0.0487

Gnomad EAS exome AF: 0.222

Gnomad FIN exome AF: 0.0626

Gnomad NFE exome AF: 0.0849

Gnomad OTH exome AF: 0.0829

GnomAD4 exome AF: 0.0822 AC: 120106 AN: 1461810 Hom.: 5702 Cov.: 32 AF XY: 0.0818 AC XY: 59521 AN XY: 727212

African (AFR) AF: 0.0358 AC: 1199 AN: 33478

American (AMR) AF: 0.0402 AC: 1799 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0511 AC: 1335 AN: 26132

East Asian (EAS) AF: 0.232 AC: 9197 AN: 39698

South Asian (SAS) AF: 0.0664 AC: 5723 AN: 86240

European-Finnish (FIN) AF: 0.0663 AC: 3540 AN: 53404

Middle Eastern (MID) AF: 0.0552 AC: 318 AN: 5764

European-Non Finnish (NFE) AF: 0.0828 AC: 92066 AN: 1111982

Other (OTH) AF: 0.0816 AC: 4929 AN: 60394

GnomAD4 genome AF: 0.0702 AC: 10669 AN: 152054 Hom.: 485 Cov.: 32 AF XY: 0.0692 AC XY: 5146 AN XY: 74326

African (AFR) AF: 0.0385 AC: 1598 AN: 41464

American (AMR) AF: 0.0563 AC: 860 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0525 AC: 182 AN: 3466

East Asian (EAS) AF: 0.225 AC: 1160 AN: 5162

South Asian (SAS) AF: 0.0714 AC: 343 AN: 4804

European-Finnish (FIN) AF: 0.0587 AC: 622 AN: 10596

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0835 AC: 5675 AN: 67978

Other (OTH) AF: 0.0737 AC: 155 AN: 2104

Alfa AF: 0.0804 Hom.: 1370

Bravo AF: 0.0682

TwinsUK AF: 0.0809 AC: 300

ALSPAC AF: 0.0843 AC: 325

ESP6500AA AF: 0.0415 AC: 183

ESP6500EA AF: 0.0812 AC: 698

ExAC AF: 0.0819 AC: 9941

Asia WGS AF: 0.114 AC: 398 AN: 3478

EpiCase AF: 0.0809

EpiControl AF: 0.0828

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	ALKALINE PHOSPHATASE, PLACENTAL, ALLELE-3 POLYMORPHISM (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.0024
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.7
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.043	D
Polyphen		1.0	D
Vest4		0.084
MPC		0.44
ClinPred		0.052	T
GERP RS		1.8
PromoterAI		-0.037	Neutral
Varity_R		0.42
gMVP		0.59
Mutation Taster		=91/9	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.87
dbscSNV1_RF	Benign	0.64
SpliceAI score (max)		0.010		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: rs1130335; hg19: chr2-233243586; COSMIC: COSV67396431; COSMIC: COSV67396431;