Variant 17-49224686-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_178500.4(PHOSPHO1):c.364T>C(p.Ser122Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PHOSPHO1
NM_178500.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.72

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.981

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PHOSPHO1	NM_178500.4 linkuse as main transcript	c.364T>C	p.Ser122Pro	missense_variant	3/3	ENST00000310544.9	NP_848595.1	Q8TCT1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PHOSPHO1	ENST00000310544.9 linkuse as main transcript	c.364T>C	p.Ser122Pro	missense_variant	3/3	2	NM_178500.4	ENSP00000311925.4	Q8TCT1-1
PHOSPHO1	ENST00000514112.1 linkuse as main transcript	c.439T>C	p.Ser147Pro	missense_variant	2/2	1		ENSP00000427694.1	Q8TCT1-3
PHOSPHO1	ENST00000413580.5 linkuse as main transcript	c.439T>C	p.Ser147Pro	missense_variant	3/3	2		ENSP00000406909.1	Q8TCT1-3
PHOSPHO1	ENST00000511066.5 linkuse as main transcript	c.364T>C	p.Ser122Pro	missense_variant	3/3	2		ENSP00000426095.1	D6RHH9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1439842

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

714778

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 02, 2024

The c.439T>C (p.S147P) alteration is located in exon 3 (coding exon 1) of the PHOSPHO1 gene. This alteration results from a T to C substitution at nucleotide position 439, causing the serine (S) at amino acid position 147 to be replaced by a proline (P). 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

0.99

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

D;.;.;.

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

D;D;.;D

M_CAP

Pathogenic

0.31

MetaRNN

Pathogenic

0.98

D;D;D;D

MetaSVM

Uncertain

0.22

MutationAssessor

Pathogenic

3.3

M;.;.;.

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-4.9

D;D;D;D

REVEL

Pathogenic

0.81

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;.

Polyphen

1.0

D;.;.;.

Vest4

0.90

MutPred

0.94

Loss of helix (P = 0.1299);.;.;Loss of helix (P = 0.1299);

MVP

0.67

ClinPred

1.0

GERP RS

5.3

Varity_R

0.93

gMVP

1.0

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

No publications associated with this variant yet.

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