rs1130335

Positions:

• chr2-232378876-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ALPP (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALPP	NM_001632.5	c.74C>T	p.Pro25Leu	missense_variant, splice_region_variant	1/11	ENST00000392027.3	NP_001623.3
LOC124906123	XR_007088121.1	n.88+69G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALPP	ENST00000392027.3	c.74C>T	p.Pro25Leu	missense_variant, splice_region_variant	1/11	1	NM_001632.5	ENSP00000375881.2
ALPP	ENST00000474529.1	n.153C>T		splice_region_variant, non_coding_transcript_exon_variant	1/4	2

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

GnomAD3 exomes AF: 0.0801 AC: 20113 AN: 251184 Hom.: 1093 AF XY: 0.0802 AC XY: 10892 AN XY: 135788

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 SAS exome AF: 0.0683

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

Gnomad4 AFR exome AF: 0.0358

Gnomad4 AMR exome AF: 0.0402

Gnomad4 ASJ exome AF: 0.0511

Gnomad4 EAS exome AF: 0.232

Gnomad4 SAS exome AF: 0.0664

Gnomad4 FIN exome AF: 0.0663

Gnomad4 NFE exome AF: 0.0828

Gnomad4 OTH exome AF: 0.0816

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

Gnomad4 AFR AF: 0.0385

Gnomad4 AMR AF: 0.0563

Gnomad4 ASJ AF: 0.0525

Gnomad4 EAS AF: 0.225

Gnomad4 SAS AF: 0.0714

Gnomad4 FIN AF: 0.0587

Gnomad4 NFE AF: 0.0835

Gnomad4 OTH AF: 0.0737

Alfa AF: 0.0768 Hom.: 426

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

ALKALINE PHOSPHATASE, PLACENTAL, ALLELE-3 POLYMORPHISM Benign:1

Benign, no assertion criteria provided

literature only

OMIM

Aug 01, 1986

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

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
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
Varity_R		0.42
gMVP		0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs1130335; hg19: chr2-233243586; COSMIC: COSV67396431; COSMIC: COSV67396431;