2-232457029-G-A

Variant names:

• chr2-232457029-G-A
• rs7559279
• NM_001631.5:c.431G>A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001631.5(ALPI):​c.431G>A​(p.Arg144His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00237 in 1,613,566 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.012 (37 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (27 hom.)
• Consequence: ALPI NM_001631.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -5.69

Genes affected

ALPI (HGNC:437): (alkaline phosphatase, intestinal) There are at least four distinct but related alkaline phosphatases: intestinal, placental, placental-like, and liver/bone/kidney (tissue non-specific). The intestinal alkaline phosphatase gene encodes a digestive brush-border enzyme. This enzyme is a component of the gut mucosal defense system and is thought to function in the detoxification of lipopolysaccharide, and in the prevention of bacterial translocation in the gut. [provided by RefSeq, Dec 2014]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048604608).
• BP6: Variant 2-232457029-G-A is Benign according to our data. Variant chr2-232457029-G-A is described in ClinVar as [Benign]. Clinvar id is 3037549.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0123 (1872/152318) while in subpopulation AFR AF= 0.0431 (1791/41554). AF 95% confidence interval is 0.0414. There are 37 homozygotes in gnomad4. There are 868 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 37 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPI	NM_001631.5	c.431G>A	p.Arg144His	missense_variant	Exon 4 of 11	ENST00000295463.4	NP_001622.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALPI	ENST00000295463.4	c.431G>A	p.Arg144His	missense_variant	Exon 4 of 11	1	NM_001631.5	ENSP00000295463.3
ALPI	ENST00000457560.1	n.*360G>A		non_coding_transcript_exon_variant	Exon 3 of 10	5		ENSP00000413068.1
ALPI	ENST00000457560.1	n.*360G>A		3_prime_UTR_variant	Exon 3 of 10	5		ENSP00000413068.1

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1863 AN: 152200 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.0430

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00379

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.00329 AC: 823 AN: 250446 Hom.: 15 AF XY: 0.00276 AC XY: 375 AN XY: 135642

Gnomad AFR exome AF: 0.0455

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.00134 AC: 1953 AN: 1461248 Hom.: 27 Cov.: 34 AF XY: 0.00121 AC XY: 876 AN XY: 726930

Gnomad4 AFR exome AF: 0.0451

Gnomad4 AMR exome AF: 0.00215

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000452

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000998

Gnomad4 OTH exome AF: 0.00303

GnomAD4 genome AF: 0.0123 AC: 1872 AN: 152318 Hom.: 37 Cov.: 32 AF XY: 0.0117 AC XY: 868 AN XY: 74474

Gnomad4 AFR AF: 0.0431

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.00493 Hom.: 12

Bravo AF: 0.0137

ESP6500AA AF: 0.0443 AC: 195

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00420 AC: 510

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

ALPI-related disorder Benign:1

May 23, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	0.0010
DANN	Benign	0.88
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.0092	N
LIST_S2	Benign	0.054	T
MetaRNN	Benign	0.0049	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.2	L
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.28
Sift	Benign	0.57	T
Sift4G	Benign	0.33	T
Polyphen		0.0090	B
Vest4		0.097
MVP		0.48
MPC		0.26
ClinPred		0.021	T
GERP RS		-11
Varity_R		0.020
gMVP		0.48

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

Publications

LitVar

Other links and lift over

dbSNP: rs7559279; hg19: chr2-233321739;