rs61778393

Variant names:

• chr1-21575943-G-T
• rs61778393
• NM_000478.6:c.1189+19G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-21575943-G-T
• chr1-21575943-G-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000478.6(ALPL):​c.1189+19G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.029 in 1,614,054 control chromosomes in the GnomAD database, including 800 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (63 hom., cov: 32)
  • Exomes 𝑓: 0.030 (737 hom.)
• Consequence: ALPL NM_000478.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.364
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-21575943-G-T is Benign according to our data. Variant chr1-21575943-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.021 (3204/152294) while in subpopulation NFE AF = 0.0348 (2369/68022). AF 95% confidence interval is 0.0337. There are 63 homozygotes in GnomAd4. There are 1459 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 63 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.1189+19G>T		intron	N/A	NP_000469.3
	ALPL	NM_001369803.2		c.1189+19G>T		intron	N/A	NP_001356732.1	P05186-1
	ALPL	NM_001369804.2		c.1189+19G>T		intron	N/A	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.1189+19G>T		intron	N/A	ENSP00000363973.3	P05186-1
	ALPL	ENST00000374832.5	TSL:2	c.1189+19G>T		intron	N/A	ENSP00000363965.1	P05186-1
	ALPL	ENST00000879459.1		c.1069+19G>T		intron	N/A	ENSP00000549518.1

Frequencies

GnomAD3 genomes AF: 0.0211 AC: 3204 AN: 152176 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.00456

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.00883

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00498

Gnomad FIN AF: 0.0261

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0348

Gnomad OTH AF: 0.0196

GnomAD2 exomes AF: 0.0218 AC: 5466 AN: 251306 AF XY: 0.0220

Gnomad AFR exome AF: 0.00535

Gnomad AMR exome AF: 0.00841

Gnomad ASJ exome AF: 0.0154

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0300

Gnomad NFE exome AF: 0.0345

Gnomad OTH exome AF: 0.0215

GnomAD4 exome AF: 0.0298 AC: 43591 AN: 1461760 Hom.: 737 Cov.: 32 AF XY: 0.0291 AC XY: 21177 AN XY: 727180

African (AFR) AF: 0.00397 AC: 133 AN: 33478

American (AMR) AF: 0.00908 AC: 406 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0155 AC: 406 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00711 AC: 613 AN: 86242

European-Finnish (FIN) AF: 0.0313 AC: 1671 AN: 53418

Middle Eastern (MID) AF: 0.00728 AC: 42 AN: 5768

European-Non Finnish (NFE) AF: 0.0350 AC: 38875 AN: 1111908

Other (OTH) AF: 0.0239 AC: 1444 AN: 60392

GnomAD4 genome AF: 0.0210 AC: 3204 AN: 152294 Hom.: 63 Cov.: 32 AF XY: 0.0196 AC XY: 1459 AN XY: 74464

African (AFR) AF: 0.00455 AC: 189 AN: 41560

American (AMR) AF: 0.00876 AC: 134 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00519 AC: 25 AN: 4820

European-Finnish (FIN) AF: 0.0261 AC: 277 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0348 AC: 2369 AN: 68022

Other (OTH) AF: 0.0194 AC: 41 AN: 2114

Alfa AF: 0.0290 Hom.: 99

Bravo AF: 0.0201

Asia WGS AF: 0.00375 AC: 14 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Hypophosphatasia (1)
-	-	1	Infantile hypophosphatasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.3
DANN	Benign	0.53
PhyloP100		-0.36
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61778393; hg19: chr1-21902436; COSMIC: COSV66376200;