NM_000478.6:c.1565T>C

Variant names:

• chr1-21577638-T-C
• rs34605986
• NM_000478.6:c.1565T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000478.6(ALPL):​c.1565T>C​(p.Val522Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 1,597,356 control chromosomes in the GnomAD database, including 9,914 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V522I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.080 (594 hom., cov: 33)
  • Exomes 𝑓: 0.11 (9320 hom.)
• Consequence: ALPL NM_000478.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:16 O:1
• Conservation: PhyloP100: -0.497
• Publications: 26 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 -19 ACMG points.

• 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=0.0013977885).
• BP6: Variant 1-21577638-T-C is Benign according to our data. Variant chr1-21577638-T-C is described in ClinVar as Benign. ClinVar VariationId is 193996.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

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.1565T>C	p.Val522Ala	missense	Exon 12 of 12	NP_000469.3
	ALPL	NM_001369803.2		c.1565T>C	p.Val522Ala	missense	Exon 12 of 12	NP_001356732.1	P05186-1
	ALPL	NM_001369804.2		c.1565T>C	p.Val522Ala	missense	Exon 12 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.1565T>C	p.Val522Ala	missense	Exon 12 of 12	ENSP00000363973.3	P05186-1
	ALPL	ENST00000374832.5	TSL:2	c.1565T>C	p.Val522Ala	missense	Exon 12 of 12	ENSP00000363965.1	P05186-1
	ALPL	ENST00000879459.1		c.1445T>C	p.Val482Ala	missense	Exon 10 of 10	ENSP00000549518.1

Frequencies

GnomAD3 genomes AF: 0.0805 AC: 12243 AN: 152130 Hom.: 590 Cov.: 33

Gnomad AFR AF: 0.0366

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.0759

Gnomad ASJ AF: 0.100

Gnomad EAS AF: 0.00328

Gnomad SAS AF: 0.152

Gnomad FIN AF: 0.0602

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.0817

GnomAD2 exomes AF: 0.0961 AC: 21977 AN: 228758 AF XY: 0.102

Gnomad AFR exome AF: 0.0339

Gnomad AMR exome AF: 0.0736

Gnomad ASJ exome AF: 0.102

Gnomad EAS exome AF: 0.00223

Gnomad FIN exome AF: 0.0559

Gnomad NFE exome AF: 0.111

Gnomad OTH exome AF: 0.0944

GnomAD4 exome AF: 0.109 AC: 158043 AN: 1445108 Hom.: 9320 Cov.: 35 AF XY: 0.111 AC XY: 79829 AN XY: 719296

African (AFR) AF: 0.0333 AC: 1111 AN: 33406

American (AMR) AF: 0.0735 AC: 3273 AN: 44504

Ashkenazi Jewish (ASJ) AF: 0.0957 AC: 2493 AN: 26042

East Asian (EAS) AF: 0.00162 AC: 64 AN: 39574

South Asian (SAS) AF: 0.164 AC: 14125 AN: 85868

European-Finnish (FIN) AF: 0.0599 AC: 2345 AN: 39158

Middle Eastern (MID) AF: 0.0782 AC: 450 AN: 5752

European-Non Finnish (NFE) AF: 0.115 AC: 128068 AN: 1110632

Other (OTH) AF: 0.102 AC: 6114 AN: 60172

GnomAD4 genome AF: 0.0804 AC: 12247 AN: 152248 Hom.: 594 Cov.: 33 AF XY: 0.0784 AC XY: 5834 AN XY: 74454

African (AFR) AF: 0.0365 AC: 1518 AN: 41546

American (AMR) AF: 0.0757 AC: 1159 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.100 AC: 348 AN: 3470

East Asian (EAS) AF: 0.00329 AC: 17 AN: 5174

South Asian (SAS) AF: 0.152 AC: 736 AN: 4830

European-Finnish (FIN) AF: 0.0602 AC: 639 AN: 10606

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.110 AC: 7494 AN: 67992

Other (OTH) AF: 0.0833 AC: 176 AN: 2114

Alfa AF: 0.0931 Hom.: 255

Bravo AF: 0.0781

TwinsUK AF: 0.114 AC: 423

ALSPAC AF: 0.112 AC: 432

ESP6500AA AF: 0.0357 AC: 155

ESP6500EA AF: 0.0967 AC: 822

ExAC AF: 0.0936 AC: 11262

Asia WGS AF: 0.0830 AC: 293 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	Hypophosphatasia (5)
-	-	4	not provided (4)
-	-	1	Adult hypophosphatasia (1)
-	-	1	Childhood hypophosphatasia (1)
-	-	1	Infantile hypophosphatasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	7.8
DANN	Benign	0.65
DEOGEN2	Benign	0.19	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.075	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.50
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.26
Sift	Benign	0.051	T
Sift4G	Uncertain	0.046	D
Polyphen		0.0030	B
Vest4		0.057
MPC		0.49
ClinPred		0.0029	T
GERP RS		-5.6
Varity_R		0.038
gMVP		0.71
Mutation Taster		=100/0	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: rs34605986; hg19: chr1-21904131; COSMIC: COSV66375923;