2-232456414-C-A

Variant names:

• chr2-232456414-C-A
• rs778354363
• NM_001631.5:c.133C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001631.5(ALPI):​c.133C>A​(p.Leu45Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ALPI NM_001631.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.278

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25211275).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALPI	NM_001631.5	c.133C>A	p.Leu45Met	missense_variant	Exon 2 of 11	ENST00000295463.4	NP_001622.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALPI	ENST00000295463.4	c.133C>A	p.Leu45Met	missense_variant	Exon 2 of 11	1	NM_001631.5	ENSP00000295463.3
ALPI	ENST00000457560.1	n.*62C>A		non_coding_transcript_exon_variant	Exon 1 of 10	5		ENSP00000413068.1
ALPI	ENST00000457560.1	n.*62C>A		3_prime_UTR_variant	Exon 1 of 10	5		ENSP00000413068.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251334 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135850

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461786 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.133C>A (p.L45M) alteration is located in exon 2 (coding exon 2) of the ALPI gene. This alteration results from a C to A substitution at nucleotide position 133, causing the leucine (L) at amino acid position 45 to be replaced by a methionine (M). 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	0.13
BayesDel_addAF	Benign	-0.0062	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.049
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	0.70	D
MutationAssessor	Pathogenic	2.9	M
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.45
Sift	Benign	0.043	D
Sift4G	Benign	0.10	T
Polyphen		0.70	P
Vest4		0.25
MutPred		0.42		Gain of catalytic residue at L45 (P = 0.0301);
MVP		0.88
MPC		0.20
ClinPred		0.53	D
GERP RS		3.7
Varity_R		0.16
gMVP		0.63

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: rs778354363; hg19: chr2-233321124;