Genetic Variant PHOSPHO1:p.Met72Leu (chr17-49224836-T-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_178500.4(PHOSPHO1):c.214A>C(p.Met72Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000413 in 1,453,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

PHOSPHO1
NM_178500.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.84

Publications

2 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:

FLJ40194 (HGNC:):

FLJ40194 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.845

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOSPHO1	NM_178500.4 link	c.214A>C	p.Met72Leu	missense_variant	Exon 3 of 3	ENST00000310544.9	NP_848595.1	Q8TCT1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHOSPHO1	ENST00000310544.9 link	c.214A>C	p.Met72Leu	missense_variant	Exon 3 of 3	2	NM_178500.4	ENSP00000311925.4		Q8TCT1-1
PHOSPHO1	ENST00000574638.1 link	c.214A>C	p.Met72Leu	missense_variant	Exon 3 of 3	3		ENSP00000461392.1		I3L4N1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000172

AC:

AN:

232856

AF XY:

0.00000790

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000174

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000173

GnomAD4 exome

AF:

0.00000413

AC:

AN:

1453676

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

722586

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33298

American (AMR)

AF:

0.00

AC:

AN:

43606

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25950

East Asian (EAS)

AF:

0.000102

AC:

AN:

39242

South Asian (SAS)

AF:

0.00

AC:

AN:

85034

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52286

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1108482

Other (OTH)

AF:

0.0000167

AC:

AN:

60024

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 18, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.289A>C (p.M97L) alteration is located in exon 3 (coding exon 1) of the PHOSPHO1 gene. This alteration results from a A to C substitution at nucleotide position 289, causing the methionine (M) at amino acid position 97 to be replaced by a leucine (L). 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

Pathogenic

0.72

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.37

T;.;.;.;.;.;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

D;D;.;D;D;D;D

M_CAP

Benign

0.039

MetaRNN

Pathogenic

0.85

D;D;D;D;D;D;D

MetaSVM

Benign

-0.42

MutationAssessor

Uncertain

2.9

M;.;.;.;.;.;.

PhyloP100

5.8

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-2.9

D;D;D;D;.;D;D

REVEL

Uncertain

0.39

Sift

Uncertain

0.013

D;D;D;D;.;D;D

Sift4G

Uncertain

0.045

D;T;T;.;.;.;.

Polyphen

0.99

D;.;.;.;.;.;.

Vest4

0.35

MutPred

0.86

Loss of methylation at K77 (P = 0.0718);.;.;Loss of methylation at K77 (P = 0.0718);Loss of methylation at K77 (P = 0.0718);.;.;

MVP

0.082

ClinPred

0.74

GERP RS

5.4

Varity_R

0.54

gMVP

0.86

Mutation Taster

=63/37

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

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chr17-49224836-T-G

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