1-21563267-G-A

Variant names:

• chr1-21563267-G-A
• rs149344982
• NM_000478.6:c.455G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 5P and 20B. PM1 PM5 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000478.6(ALPL):​c.455G>A​(p.Arg152His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 1,612,314 control chromosomes in the GnomAD database, including 226 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R152C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0090 (13 hom., cov: 33)
  • Exomes 𝑓: 0.013 (213 hom.)
• Consequence: ALPL NM_000478.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21 O:1
• Conservation: PhyloP100: 0.283
• Publications: 27 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: Benign. The variant received -15 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_000478.6
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-21563266-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1470828.
• 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 adult hypophosphatasia, infantile hypophosphatasia, odontohypophosphatasia, childhood hypophosphatasia, hypophosphatasia, perinatal lethal hypophosphatasia.
• BP4: Computational evidence support a benign effect (MetaRNN=0.006093651).
• BP6: Variant 1-21563267-G-A is Benign according to our data. Variant chr1-21563267-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 197679.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00896 (1361/151928) while in subpopulation SAS AF = 0.032 (154/4808). AF 95% confidence interval is 0.0279. There are 13 homozygotes in GnomAd4. There are 677 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AD,AR gene

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.455G>A	p.Arg152His	missense	Exon 5 of 12	NP_000469.3
	ALPL	NM_001369803.2		c.455G>A	p.Arg152His	missense	Exon 5 of 12	NP_001356732.1	P05186-1
	ALPL	NM_001369804.2		c.455G>A	p.Arg152His	missense	Exon 5 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.455G>A	p.Arg152His	missense	Exon 5 of 12	ENSP00000363973.3	P05186-1
	ALPL	ENST00000374832.5	TSL:2	c.455G>A	p.Arg152His	missense	Exon 5 of 12	ENSP00000363965.1	P05186-1
	ALPL	ENST00000879459.1		c.335G>A	p.Arg112His	missense	Exon 3 of 10	ENSP00000549518.1

Frequencies

GnomAD3 genomes AF: 0.00898 AC: 1364 AN: 151810 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.00261

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00742

Gnomad ASJ AF: 0.00982

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0326

Gnomad FIN AF: 0.00680

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0124

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.0115 AC: 2872 AN: 249266 AF XY: 0.0133

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.00629

Gnomad ASJ exome AF: 0.00752

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.00788

Gnomad NFE exome AF: 0.0126

Gnomad OTH exome AF: 0.0122

GnomAD4 exome AF: 0.0132 AC: 19300 AN: 1460386 Hom.: 213 Cov.: 37 AF XY: 0.0138 AC XY: 10023 AN XY: 726352

African (AFR) AF: 0.00212 AC: 71 AN: 33468

American (AMR) AF: 0.00676 AC: 302 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00752 AC: 196 AN: 26072

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39682

South Asian (SAS) AF: 0.0302 AC: 2599 AN: 86180

European-Finnish (FIN) AF: 0.00772 AC: 409 AN: 53008

Middle Eastern (MID) AF: 0.0239 AC: 137 AN: 5740

European-Non Finnish (NFE) AF: 0.0132 AC: 14670 AN: 1111220

Other (OTH) AF: 0.0151 AC: 911 AN: 60322

GnomAD4 genome AF: 0.00896 AC: 1361 AN: 151928 Hom.: 13 Cov.: 33 AF XY: 0.00912 AC XY: 677 AN XY: 74260

African (AFR) AF: 0.00260 AC: 108 AN: 41468

American (AMR) AF: 0.00741 AC: 113 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00982 AC: 34 AN: 3464

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5184

South Asian (SAS) AF: 0.0320 AC: 154 AN: 4808

European-Finnish (FIN) AF: 0.00680 AC: 72 AN: 10586

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0124 AC: 841 AN: 67860

Other (OTH) AF: 0.0133 AC: 28 AN: 2108

Alfa AF: 0.00961 Hom.: 11

Bravo AF: 0.00791

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.0117 AC: 45

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0144 AC: 124

ExAC AF: 0.0112 AC: 1363

Asia WGS AF: 0.0120 AC: 40 AN: 3478

EpiCase AF: 0.0165

EpiControl AF: 0.0170

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	5	not specified (5)
-	-	4	Hypophosphatasia (5)
-	-	1	Adult hypophosphatasia (1)
-	-	1	Childhood hypophosphatasia (1)
-	-	1	Childhood hypophosphatasia;C0268412:Infantile hypophosphatasia;C0268413:Adult hypophosphatasia (1)
-	-	1	Infantile hypophosphatasia (1)
-	-	1	Osteogenesis imperfecta (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.68	T
MetaRNN	Benign	0.0061	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.28
PrimateAI	Benign	0.28	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.26
Sift	Benign	0.43	T
Sift4G	Benign	0.23	T
Polyphen		0.072	B
Vest4		0.063
MPC		0.56
ClinPred		0.011	T
GERP RS		2.6
Varity_R		0.039
gMVP		0.76
Mutation Taster		=95/5	polymorphism (auto)

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: rs149344982; hg19: chr1-21889760;