Genetic Variant PHOSPHO1:p.Arg230Ser (chr17-49224362-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_178500.4(PHOSPHO1):c.688C>A(p.Arg230Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000283 in 1,411,824 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R230C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

PHOSPHO1
NM_178500.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.44

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.39060557).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOSPHO1	NM_178500.4 link	c.688C>A	p.Arg230Ser	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.688C>A	p.Arg230Ser	missense_variant	Exon 3 of 3	2	NM_178500.4	ENSP00000311925.4	Q8TCT1-1
PHOSPHO1	ENST00000514112.1 link	c.763C>A	p.Arg255Ser	missense_variant	Exon 2 of 2	1		ENSP00000427694.1	Q8TCT1-3
PHOSPHO1	ENST00000413580.5 link	c.763C>A	p.Arg255Ser	missense_variant	Exon 3 of 3	2		ENSP00000406909.1	Q8TCT1-3
PHOSPHO1	ENST00000511066.5 link	c.*77C>A		downstream_gene_variant		2		ENSP00000426095.1	D6RHH9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000283

AC:

AN:

1411824

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

699122

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32332

American (AMR)

AF:

0.00

AC:

AN:

37908

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25380

East Asian (EAS)

AF:

0.00

AC:

AN:

36940

South Asian (SAS)

AF:

0.00

AC:

AN:

81442

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43330

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5592

European-Non Finnish (NFE)

AF:

0.00000367

AC:

AN:

1090262

Other (OTH)

AF:

0.00

AC:

AN:

58638

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 23, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.763C>A (p.R255S) alteration is located in exon 3 (coding exon 1) of the PHOSPHO1 gene. This alteration results from a C to A substitution at nucleotide position 763, causing the arginine (R) at amino acid position 255 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

Uncertain

0.47

BayesDel_addAF

Benign

-0.040

BayesDel_noAF

Benign

-0.30

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;.;.

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.91

D;D;.

M_CAP

Benign

0.040

MetaRNN

Benign

0.39

T;T;T

MetaSVM

Benign

-0.65

MutationAssessor

Uncertain

2.0

M;.;.

PhyloP100

4.4

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-2.7

D;D;D

REVEL

Benign

0.22

Sift

Uncertain

0.0040

D;D;D

Sift4G

Uncertain

0.023

D;D;D

Polyphen

0.97

D;.;.

Vest4

0.35

MutPred

0.56

Gain of disorder (P = 0.0922);.;.;

MVP

0.068

ClinPred

0.99

GERP RS

4.5

Varity_R

0.68

gMVP

0.75

Mutation Taster

=78/22

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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chr17-49224362-G-T

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