Variant 17-49224406-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_178500.4(PHOSPHO1):c.644C>T(p.Ala215Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000135 in 1,551,956 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 (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

PHOSPHO1
NM_178500.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.09

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.03482598).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHOSPHO1	NM_178500.4 linkuse as main transcript	c.644C>T	p.Ala215Val	missense_variant	3/3	ENST00000310544.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHOSPHO1	ENST00000310544.9 linkuse as main transcript	c.644C>T	p.Ala215Val	missense_variant	3/3	2	NM_178500.4	P1	Q8TCT1-1
PHOSPHO1	ENST00000514112.1 linkuse as main transcript	c.719C>T	p.Ala240Val	missense_variant	2/2	1			Q8TCT1-3
PHOSPHO1	ENST00000413580.5 linkuse as main transcript	c.719C>T	p.Ala240Val	missense_variant	3/3	2			Q8TCT1-3
PHOSPHO1	ENST00000511066.5 linkuse as main transcript			downstream_gene_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000539

AC:

AN:

148334

Hom.:

AF XY:

0.0000123

AC XY:

AN XY:

81154

show subpopulations

Gnomad AFR exome

AF:

0.000135

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000446

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000350

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000121

AC:

AN:

1399602

Hom.:

Cov.:

AF XY:

0.0000116

AC XY:

AN XY:

691618

show subpopulations

Gnomad4 AFR exome

AF:

0.0000941

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000249

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000369

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152354

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.0000721

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ExAC

AF:

0.0000268

AC:

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 20, 2023

The c.719C>T (p.A240V) 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 719, causing the alanine (A) at amino acid position 240 to be replaced by a valine (V). 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

0.13

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

T;.;.

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.83

T;T;.

M_CAP

Benign

0.0076

MetaRNN

Benign

0.035

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.7

L;.;.

MutationTaster

Benign

0.60

N;N;N

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.9

N;N;N

REVEL

Benign

0.12

Sift

Benign

0.18

T;T;T

Sift4G

Benign

0.13

T;T;T

Polyphen

0.91

P;.;.

Vest4

0.14

MutPred

0.55

Gain of sheet (P = 0.0477);.;.;

MVP

0.043

ClinPred

0.083

GERP RS

5.5

Varity_R

0.18

gMVP

0.68

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over