Genetic Variant PHOSPHO1:p.Gly17Ser (chr17-49225001-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_178500.4(PHOSPHO1):c.49G>A(p.Gly17Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000197 in 1,522,314 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G17R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

PHOSPHO1
NM_178500.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0220

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOSPHO1	NM_178500.4 link	c.49G>A	p.Gly17Ser	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.49G>A	p.Gly17Ser	missense_variant	Exon 3 of 3	2	NM_178500.4	ENSP00000311925.4		Q8TCT1-1
PHOSPHO1	ENST00000574638.1 link	c.49G>A	p.Gly17Ser	missense_variant	Exon 3 of 3	3		ENSP00000461392.1		I3L4N1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

131054

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.30e-7

AC:

AN:

1370100

Hom.:

Cov.:

AF XY:

0.00000149

AC XY:

AN XY:

673076

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31486

American (AMR)

AF:

0.00

AC:

AN:

34234

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22962

East Asian (EAS)

AF:

0.00

AC:

AN:

36572

South Asian (SAS)

AF:

0.00

AC:

AN:

75036

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40236

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5548

European-Non Finnish (NFE)

AF:

9.37e-7

AC:

AN:

1067118

Other (OTH)

AF:

0.00

AC:

AN:

56908

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41464

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Oct 17, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.124G>A (p.G42S) alteration is located in exon 3 (coding exon 1) of the PHOSPHO1 gene. This alteration results from a G to A substitution at nucleotide position 124, causing the glycine (G) at amino acid position 42 to be replaced by a serine (S). 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

0.099

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.055

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

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.65

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

M_CAP

Benign

0.012

MetaRNN

Benign

0.040

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;.;.;.;.;.;.

PhyloP100

0.022

PrimateAI

Benign

0.40

PROVEAN

Benign

0.11

N;N;N;N;.;N;N

REVEL

Benign

0.034

Sift

Benign

0.25

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

Sift4G

Benign

0.46

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

Polyphen

0.0

B;.;.;.;.;.;.

Vest4

0.11

MutPred

0.27

Gain of phosphorylation at G17 (P = 0.0236);.;.;Gain of phosphorylation at G17 (P = 0.0236);Gain of phosphorylation at G17 (P = 0.0236);.;.;

MVP

0.043

ClinPred

0.10

GERP RS

2.0

Varity_R

0.060

gMVP

0.24

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.42

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.42

Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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17-49225001-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over