Genetic Variant PHOSPHO1:p.Arg26His (chr17-49224973-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.77G>A(p.Arg26His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,404,556 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R26P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PHOSPHO1
NM_178500.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.35

Publications

0 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 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.77G>A	p.Arg26His	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.77G>A	p.Arg26His	missense_variant	Exon 3 of 3	2	NM_178500.4	ENSP00000311925.4		Q8TCT1-1
PHOSPHO1	ENST00000574638.1 link	c.77G>A	p.Arg26His	missense_variant	Exon 3 of 3	3		ENSP00000461392.1		I3L4N1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000142

AC:

AN:

1404556

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

693690

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32266

American (AMR)

AF:

0.00

AC:

AN:

37750

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24580

East Asian (EAS)

AF:

0.00

AC:

AN:

37624

South Asian (SAS)

AF:

0.00

AC:

AN:

80642

European-Finnish (FIN)

AF:

0.0000226

AC:

AN:

44268

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5640

European-Non Finnish (NFE)

AF:

9.23e-7

AC:

AN:

1083572

Other (OTH)

AF:

0.00

AC:

AN:

58214

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.015

BayesDel_noAF

Benign

-0.26

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.56

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

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.89

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

M_CAP

Benign

0.085

MetaRNN

Uncertain

0.73

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

MetaSVM

Benign

-0.65

MutationAssessor

Uncertain

2.6

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

PhyloP100

2.3

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.2

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

REVEL

Uncertain

0.34

Sift

Uncertain

0.0030

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

Sift4G

Uncertain

0.0080

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

Polyphen

1.0

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

Vest4

0.23

MutPred

0.77

Loss of MoRF binding (P = 0.0744);.;.;Loss of MoRF binding (P = 0.0744);Loss of MoRF binding (P = 0.0744);.;.;

MVP

0.11

ClinPred

0.99

GERP RS

4.5

Varity_R

0.24

gMVP

0.54

Mutation Taster

=80/20

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over