chr1-21568242-T-C

Variant names:

• chr1-21568242-T-C
• rs3200254
• NM_000478.6:c.787T>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000478.6(ALPL):​c.787T>C​(p.Tyr263His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.144 in 1,613,726 control chromosomes in the GnomAD database, including 21,866 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 (★★). Synonymous variant affecting the same amino acid position (i.e. Y263Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.18 (3121 hom., cov: 31)
  • Exomes 𝑓: 0.14 (18745 hom.)
• Consequence: ALPL NM_000478.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17 O:1
• Conservation: PhyloP100: 0.0570
• Publications: 48 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 -17 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000478.6
• 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=0.0024879575).
• BP6: Variant 1-21568242-T-C is Benign according to our data. Variant chr1-21568242-T-C is described in ClinVar as Benign. ClinVar VariationId is 198423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.438 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.787T>C	p.Tyr263His	missense	Exon 7 of 12	NP_000469.3
	ALPL	NM_001369803.2		c.787T>C	p.Tyr263His	missense	Exon 7 of 12	NP_001356732.1	P05186-1
	ALPL	NM_001369804.2		c.787T>C	p.Tyr263His	missense	Exon 7 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.787T>C	p.Tyr263His	missense	Exon 7 of 12	ENSP00000363973.3	P05186-1
	ALPL	ENST00000374832.5	TSL:2	c.787T>C	p.Tyr263His	missense	Exon 7 of 12	ENSP00000363965.1	P05186-1
	ALPL	ENST00000879459.1		c.667T>C	p.Tyr223His	missense	Exon 5 of 10	ENSP00000549518.1

Frequencies

GnomAD3 genomes AF: 0.183 AC: 27756 AN: 151812 Hom.: 3108 Cov.: 31

Gnomad AFR AF: 0.251

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.451

Gnomad SAS AF: 0.233

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.118

Gnomad NFE AF: 0.111

Gnomad OTH AF: 0.177

GnomAD2 exomes AF: 0.183 AC: 46072 AN: 251140 AF XY: 0.178

Gnomad AFR exome AF: 0.256

Gnomad AMR exome AF: 0.251

Gnomad ASJ exome AF: 0.137

Gnomad EAS exome AF: 0.445

Gnomad FIN exome AF: 0.183

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.157

GnomAD4 exome AF: 0.140 AC: 205273 AN: 1461796 Hom.: 18745 Cov.: 33 AF XY: 0.141 AC XY: 102884 AN XY: 727200

African (AFR) AF: 0.265 AC: 8867 AN: 33478

American (AMR) AF: 0.246 AC: 10997 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 3627 AN: 26136

East Asian (EAS) AF: 0.511 AC: 20277 AN: 39698

South Asian (SAS) AF: 0.217 AC: 18714 AN: 86250

European-Finnish (FIN) AF: 0.175 AC: 9365 AN: 53396

Middle Eastern (MID) AF: 0.131 AC: 753 AN: 5762

European-Non Finnish (NFE) AF: 0.111 AC: 123329 AN: 1111972

Other (OTH) AF: 0.155 AC: 9344 AN: 60394

GnomAD4 genome AF: 0.183 AC: 27806 AN: 151930 Hom.: 3121 Cov.: 31 AF XY: 0.191 AC XY: 14155 AN XY: 74258

African (AFR) AF: 0.252 AC: 10420 AN: 41428

American (AMR) AF: 0.224 AC: 3420 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 487 AN: 3466

East Asian (EAS) AF: 0.453 AC: 2325 AN: 5132

South Asian (SAS) AF: 0.233 AC: 1120 AN: 4812

European-Finnish (FIN) AF: 0.188 AC: 1981 AN: 10540

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 292

European-Non Finnish (NFE) AF: 0.111 AC: 7529 AN: 67970

Other (OTH) AF: 0.181 AC: 383 AN: 2114

Alfa AF: 0.142 Hom.: 4822

Bravo AF: 0.190

TwinsUK AF: 0.105 AC: 388

ALSPAC AF: 0.113 AC: 434

ESP6500AA AF: 0.252 AC: 1109

ESP6500EA AF: 0.111 AC: 956

ExAC AF: 0.179 AC: 21693

Asia WGS AF: 0.327 AC: 1135 AN: 3478

EpiCase AF: 0.108

EpiControl AF: 0.110

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)
-	-	1	Osteogenesis imperfecta (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	9.8
DANN	Benign	0.69
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.071	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.070	N
PhyloP100		0.057
PrimateAI	Benign	0.39	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.19
Sift	Benign	1.0	T
Sift4G	Benign	0.59	T
Polyphen		0.0	B
Vest4		0.037
MPC		0.53
ClinPred		0.00041	T
GERP RS		1.9
Varity_R		0.031
gMVP		0.72
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: rs3200254; hg19: chr1-21894735; COSMIC: COSV66376916; COSMIC: COSV66376916;