rs199669988

Variant names:

• chr1-21564097-G-A
• rs199669988
• NM_000478.6:c.529G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-21564097-G-A
• chr1-21564097-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 10P and 2B. PS3 PM1 PM5 PP2 PP5 BP4 BS2_Supporting

The NM_000478.6(ALPL):​c.529G>A​(p.Ala177Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000209 in 1,614,044 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000914389: In vitro functional studies conducted in several different cell lines suggest that the p.Ala177Thr variant does not affect protein expression relative to wild type but does have a moderate effect on protein function (Orimo et al. 2001" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A177V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (4 hom.)
• Consequence: ALPL NM_000478.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6 U:6
• Conservation: PhyloP100: 1.48
• Publications: 13 publications found

Genes affected

ALPL (HGNC:438): (alkaline phosphatase, biomineralization associated) This gene encodes a member of the alkaline phosphatase family of proteins. There are at least four distinct but related alkaline phosphatases: intestinal, placental, placental-like, and liver/bone/kidney (tissue non-specific). The first three are located together on chromosome 2, while the tissue non-specific form is located on chromosome 1. The product of this gene is a membrane bound glycosylated enzyme that is not expressed in any particular tissue and is, therefore, referred to as the tissue-nonspecific form of the enzyme. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature enzyme. This enzyme may play a role in bone mineralization. Mutations in this gene have been linked to hypophosphatasia, a disorder that is characterized by hypercalcemia and skeletal defects. [provided by RefSeq, Oct 2015]

ALPL Gene-Disease associations (from GenCC):

• adult hypophosphatasia

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• ALPL-related autosomal dominant hypophosphatasia

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• childhood hypophosphatasia

  Inheritance: AD, AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Laboratory for Molecular Medicine, ClinGen
• ALPL-related autosomal recessive hypophosphatasia

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• hypophosphatasia

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, G2P
• infantile hypophosphatasia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
• odontohypophosphatasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• perinatal lethal hypophosphatasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000914389: In vitro functional studies conducted in several different cell lines suggest that the p.Ala177Thr variant does not affect protein expression relative to wild type but does have a moderate effect on protein function (Orimo et al. 2001; Di Mauro et al. 2002; Orimo et al. 2008).; SCV000946314: Experimental studies have shown that this missense change affects ALPL function (PMID: 11760847, 12162492, 18455459).
• PM1: In a hotspot region, there are 18 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000478.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-21564098-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 427764.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 220 curated pathogenic missense variants (we use a threshold of 10). The gene has 10 curated benign missense variants. Gene score misZ: 1.2672 (below the threshold of 3.09). Trascript score misZ: 1.9021 (below the threshold of 3.09). GenCC associations: The gene is linked to ALPL-related autosomal dominant hypophosphatasia, ALPL-related autosomal recessive hypophosphatasia, infantile hypophosphatasia, hypophosphatasia, adult hypophosphatasia, odontohypophosphatasia, childhood hypophosphatasia, perinatal lethal hypophosphatasia.
• PP5: Variant 1-21564097-G-A is Pathogenic according to our data. Variant chr1-21564097-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 556961.
• BP4: Computational evidence support a benign effect (MetaRNN=0.10656512). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAdExome4 at 4 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000478.6. 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
	ALPL	NM_000478.6	MANE Select	c.529G>A	p.Ala177Thr	missense	Exon 6 of 12	NP_000469.3
	ALPL	NM_001369803.2		c.529G>A	p.Ala177Thr	missense	Exon 6 of 12	NP_001356732.1	P05186-1
	ALPL	NM_001369804.2		c.529G>A	p.Ala177Thr	missense	Exon 6 of 12	NP_001356733.1	P05186-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALPL	ENST00000374840.8	TSL:1 MANE Select	c.529G>A	p.Ala177Thr	missense	Exon 6 of 12	ENSP00000363973.3	P05186-1
	ALPL	ENST00000374832.5	TSL:2	c.529G>A	p.Ala177Thr	missense	Exon 6 of 12	ENSP00000363965.1	P05186-1
	ALPL	ENST00000879459.1		c.409G>A	p.Ala137Thr	missense	Exon 4 of 10	ENSP00000549518.1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00289

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000131 AC: 33 AN: 251080 AF XY: 0.000140

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00158

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000220 AC: 321 AN: 1461756 Hom.: 4 Cov.: 32 AF XY: 0.000209 AC XY: 152 AN XY: 727190

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26134

East Asian (EAS) AF: 0.00771 AC: 306 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111990

Other (OTH) AF: 0.0000497 AC: 3 AN: 60392

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152288 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74452

African (AFR) AF: 0.00 AC: 0 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

East Asian (EAS) AF: 0.00289 AC: 15 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000133 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.000132 AC: 16

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	-	Hypophosphatasia (3)
1	1	-	Adult hypophosphatasia (2)
2	-	-	not provided (2)
1	-	-	Childhood hypophosphatasia;C0268412:Infantile hypophosphatasia;C0268413:Adult hypophosphatasia (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	Infantile hypophosphatasia (1)
-	1	-	Microcephaly (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Uncertain	0.090
CADD	Benign	8.8
DANN	Benign	0.21
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.70
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.11	T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	0.88	L
PhyloP100		1.5
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.12	N
REVEL	Uncertain	0.58
Sift	Benign	0.70	T
Sift4G	Benign	0.80	T
Polyphen		0.14	B
Vest4		0.77
MVP		0.83
MPC		0.46
ClinPred		0.029	T
GERP RS		2.0
Varity_R		0.094
gMVP		0.92
Mutation Taster		=2/98	disease causing (ClinVar)

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: rs199669988; hg19: chr1-21890590; COSMIC: COSV66379484;