2-232457014-A-G

Variant names:

• chr2-232457014-A-G
• rs769179073
• NM_001631.5:c.416A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001631.5(ALPI):​c.416A>G​(p.Gln139Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 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. Q139P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ALPI NM_001631.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.12
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33992893).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001631.5. 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
	ALPI	NM_001631.5	MANE Select	c.416A>G	p.Gln139Arg	missense	Exon 4 of 11	NP_001622.2	P09923

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALPI	ENST00000295463.4	TSL:1 MANE Select	c.416A>G	p.Gln139Arg	missense	Exon 4 of 11	ENSP00000295463.3	P09923
	ALPI	ENST00000457560.1	TSL:5	n.*345A>G		non_coding_transcript_exon	Exon 3 of 10	ENSP00000413068.1	F8WEQ0
	ALPI	ENST00000457560.1	TSL:5	n.*345A>G		3_prime_UTR	Exon 3 of 10	ENSP00000413068.1	F8WEQ0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461296 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726954

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52870

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111992

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	18
DANN	Benign	0.88
DEOGEN2	Uncertain	0.68	D
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.62	T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	0.0078	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.1
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.37
Sift	Benign	0.27	T
Sift4G	Benign	0.35	T
Polyphen		0.016	B
Vest4		0.083
MutPred		0.48		Gain of helix (P = 0.0078)
MVP		0.79
MPC		0.23
ClinPred		0.35	T
GERP RS		5.3
Varity_R		0.14
gMVP		0.72
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs769179073; hg19: chr2-233321724;