Genetic Variant PHOSPHO1:p.Ala215Val (chr17-49224406-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_178500.4(PHOSPHO1):c.644C>T(p.Ala215Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000135 in 1,551,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

PHOSPHO1
NM_178500.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.09

Publications

1 publications found

Variant links:

Genes affected

PHOSPHO1 (HGNC:16815): (phosphoethanolamine/phosphocholine phosphatase 1) Enables pyrophosphatase activity. Predicted to be involved in bone mineralization involved in bone maturation. Predicted to act upstream of or within endochondral ossification. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

PHOSPHO1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.03482598).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOSPHO1	NM_178500.4 link	c.644C>T	p.Ala215Val	missense_variant	Exon 3 of 3	ENST00000310544.9	NP_848595.1	Q8TCT1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PHOSPHO1	ENST00000310544.9 link	c.644C>T	p.Ala215Val	missense_variant	Exon 3 of 3	2	NM_178500.4	ENSP00000311925.4	Q8TCT1-1
PHOSPHO1	ENST00000514112.1 link	c.719C>T	p.Ala240Val	missense_variant	Exon 2 of 2	1		ENSP00000427694.1	Q8TCT1-3
PHOSPHO1	ENST00000413580.5 link	c.719C>T	p.Ala240Val	missense_variant	Exon 3 of 3	2		ENSP00000406909.1	Q8TCT1-3
PHOSPHO1	ENST00000511066.5 link	c.*33C>T		downstream_gene_variant		2		ENSP00000426095.1	D6RHH9

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000539

AC:

AN:

148334

AF XY:

0.0000123

show subpopulations

Gnomad AFR exome

AF:

0.000135

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000446

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000350

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000121

AC:

AN:

1399602

Hom.:

Cov.:

AF XY:

0.0000116

AC XY:

AN XY:

691618

show subpopulations

African (AFR)

AF:

0.0000941

AC:

AN:

31894

American (AMR)

AF:

0.00

AC:

AN:

36342

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25206

East Asian (EAS)

AF:

0.000249

AC:

AN:

36184

South Asian (SAS)

AF:

0.00

AC:

AN:

80312

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43250

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5192

European-Non Finnish (NFE)

AF:

0.00000369

AC:

AN:

1083118

Other (OTH)

AF:

0.0000172

AC:

AN:

58104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152354

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0000721

AC:

AN:

41594

American (AMR)

AF:

0.00

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000268

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 20, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.719C>T (p.A240V) alteration is located in exon 3 (coding exon 1) of the PHOSPHO1 gene. This alteration results from a C to T substitution at nucleotide position 719, causing the alanine (A) at amino acid position 240 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

T;.;.

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.83

T;T;.

M_CAP

Benign

0.0076

MetaRNN

Benign

0.035

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.7

L;.;.

PhyloP100

3.1

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.9

N;N;N

REVEL

Benign

0.12

Sift

Benign

0.18

T;T;T

Sift4G

Benign

0.13

T;T;T

Polyphen

0.91

P;.;.

Vest4

0.14

MutPred

0.55

Gain of sheet (P = 0.0477);.;.;

MVP

0.043

ClinPred

0.083

GERP RS

5.5

Varity_R

0.18

gMVP

0.68

Mutation Taster

=92/8

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

chr17-49224406-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over