NM_000478.6:c.571G>A

Variant names:

• chr1-21564139-G-A
• rs121918007
• NM_000478.6:c.571G>A

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 17P and 2B. PS3 PM1 PM5 PP2 PP5_Very_Strong BP4 BS2_Supporting

The NM_000478.6(ALPL):​c.571G>A​(p.Glu191Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00141 in 1,614,074 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002104243: "In vitro functional studies have suggested this variant mildly reduced the alkaline phosphatase (ALP) activity." PMID:24569605" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E191G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (9 hom.)
• Consequence: ALPL NM_000478.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:42 O:1
• Conservation: PhyloP100: 4.64
• Publications: 70 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: Pathogenic. The variant received 15 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002104243: "In vitro functional studies have suggested this variant mildly reduced the alkaline phosphatase (ALP) activity." PMID:24569605; SCV005399130: Site directed mutagenesis studies have shown this variant has residual activity of 56% compared to wild type and is thought to be a moderate allele (PMID: 19500388).; SCV000914390: "In vitro functional studies performed by Fauvert et al. (2009) showed that the p.Glu191Lys variant has a residual activity of 56% compared to wild type." PMID:29933521; SCV001142293: Functional studies demonstrate that c.571G>A has reduced alkaline phosphatase activity due to structural disturbances and delay in membrane anchoring (PMID:17719863).; SCV006334912: At least one functional study has demonstrated a substantial alteration in protein function relative to the wild-type (PMID:32160374).; SCV000617526: Published functional studies demonstrate that E191K has delayed membrane anchoring (Brun-Heath et al., 2007) and relatively high residual alkaline phosphatase activity (56% and 88% of wildtype), though no dominant negative effect was observed (Zurutuza et al., 1999; Fauvert et al., 2009; Hofmann et al., 2014); PMID: 24569605, 20739387, 1409720, 19500388, 11855933, 10332035, 18328985, 17719863, 11438998, 12357339, 29659871, 10679946, 19232125, 27920814, 10737975, 29236161, 15671102, 32160374, 31589614, 33083013, 8606878, 33101980, 34213743, 33093890, 33549410; SCV000950872: Experimental studies have shown that this missense change affects ALPL function (PMID: 1409720, 20739387, 24569605).; SCV005414127: PS3; SCV003730807: Multiple in vitro functional studies using transient expression in cells show slightly reduced activity consistent with a mild loss of function allele based on comparison to wild type and pathogenic controls (Hofmann, 2014; Zurutuza, 1999; Del Angel, 2020).; SCV005344780: Functional studies using COS7 and HEK293 cells show mild reduction in tissue non-specific alkaline phosphatase (TNSALP) activity and also indicate this variant does not result in a dominant-negative effect. Fauvert et al. 2009. PubMed ID: 19500388; Hofmann et al. 2014. PubMed ID: 24569605).; SCV006561131: "Well-established in vitro and in vivo functional studies supportive of damaging effect on the gene product, with low residual enzymatic activity relative to wild-type reported (PMID: 1409720, 20739387, 24569605, 32160374)"
• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000478.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-21564140-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1455023.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 1-21564139-G-A is Pathogenic according to our data. Variant chr1-21564139-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 13670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.014826685). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAdExome4 at 9 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.571G>A	p.Glu191Lys	missense	Exon 6 of 12	NP_000469.3
	ALPL	NM_001369803.2		c.571G>A	p.Glu191Lys	missense	Exon 6 of 12	NP_001356732.1	P05186-1
	ALPL	NM_001369804.2		c.571G>A	p.Glu191Lys	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.571G>A	p.Glu191Lys	missense	Exon 6 of 12	ENSP00000363973.3	P05186-1
	ALPL	ENST00000374832.5	TSL:2	c.571G>A	p.Glu191Lys	missense	Exon 6 of 12	ENSP00000363965.1	P05186-1
	ALPL	ENST00000879459.1		c.451G>A	p.Glu151Lys	missense	Exon 4 of 10	ENSP00000549518.1

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 285 AN: 152160 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0170

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00138

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00244 AC: 613 AN: 251204 AF XY: 0.00254

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0171

Gnomad NFE exome AF: 0.00202

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00137 AC: 1996 AN: 1461796 Hom.: 9 Cov.: 32 AF XY: 0.00134 AC XY: 976 AN XY: 727204

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

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

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.0163 AC: 870 AN: 53356

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

European-Non Finnish (NFE) AF: 0.000922 AC: 1025 AN: 1111992

Other (OTH) AF: 0.00151 AC: 91 AN: 60396

GnomAD4 genome AF: 0.00187 AC: 285 AN: 152278 Hom.: 1 Cov.: 32 AF XY: 0.00255 AC XY: 190 AN XY: 74458

African (AFR) AF: 0.0000962 AC: 4 AN: 41568

American (AMR) AF: 0.000262 AC: 4 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.0170 AC: 180 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00138 AC: 94 AN: 68012

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00100 Hom.: 1

Bravo AF: 0.000578

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00257 AC: 312

EpiCase AF: 0.00109

EpiControl AF: 0.00124

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
15	-	-	not provided (15)
6	-	-	Childhood hypophosphatasia (6)
6	-	-	Hypophosphatasia (7)
4	-	-	Adult hypophosphatasia (4)
3	-	-	Infantile hypophosphatasia (3)
2	-	-	Childhood hypophosphatasia;C0268412:Infantile hypophosphatasia;C0268413:Adult hypophosphatasia (2)
1	-	-	ALPL-related disorder (1)
1	-	-	Hypophosphatasia;C0220743:Childhood hypophosphatasia;C0268412:Infantile hypophosphatasia;C0268413:Adult hypophosphatasia (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Odontohypophosphatasia (1)
1	-	-	Osteogenesis imperfecta (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.015	T
MetaSVM	Pathogenic	0.89	D
MutationAssessor	Benign	1.5	L
PhyloP100		4.6
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.84
Sift	Benign	0.058	T
Sift4G	Benign	0.21	T
Polyphen		0.97	D
Vest4		0.91
MVP		0.95
MPC		1.1
ClinPred		0.084	T
GERP RS		5.2
Varity_R		0.30
gMVP		0.89
Mutation Taster		=77/23	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: rs121918007; hg19: chr1-21890632;