Genetic Variant PHOSPHO1:p.Pro9Leu (chr17-49225099-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001143804.2(PHOSPHO1):c.26C>T(p.Pro9Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PHOSPHO1
NM_001143804.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.73

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07931581).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOSPHO1	NM_178500.4 link	c.46-95C>T		intron_variant	Intron 2 of 2	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.46-95C>T		intron_variant	Intron 2 of 2	2	NM_178500.4	ENSP00000311925.4		Q8TCT1-1
PHOSPHO1	ENST00000574638.1 link	c.46-95C>T		intron_variant	Intron 2 of 2	3		ENSP00000461392.1		I3L4N1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1290642

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

626884

African (AFR)

AF:

0.00

AC:

AN:

28284

American (AMR)

AF:

0.00

AC:

AN:

19744

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18902

East Asian (EAS)

AF:

0.00

AC:

AN:

34990

South Asian (SAS)

AF:

0.00

AC:

AN:

63256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4840

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1036318

Other (OTH)

AF:

0.00

AC:

AN:

53702

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 01, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.26C>T (p.P9L) 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 26, causing the proline (P) at amino acid position 9 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

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.061

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.60

T;.;T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.079

T;T;T;T

MetaSVM

Benign

-1.0

PhyloP100

2.7

PROVEAN

Benign

-0.48

N;N;N;N

REVEL

Benign

0.11

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;.;.

Vest4

0.17

MutPred

0.21

Gain of helix (P = 0.005);Gain of helix (P = 0.005);Gain of helix (P = 0.005);.;

MVP

0.043

ClinPred

0.66

GERP RS

4.0

gMVP

0.20

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over