17-49224550-C-G

Variant names:

• chr17-49224550-C-G
• NM_178500.4:c.500G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_178500.4(PHOSPHO1):​c.500G>C​(p.Ser167Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PHOSPHO1 NM_178500.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.457
• Publications: 0 publications found

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]

FLJ40194 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22048512).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOSPHO1	NM_178500.4	c.500G>C	p.Ser167Thr	missense_variant	Exon 3 of 3	ENST00000310544.9	NP_848595.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHOSPHO1	ENST00000310544.9	c.500G>C	p.Ser167Thr	missense_variant	Exon 3 of 3	2	NM_178500.4	ENSP00000311925.4
PHOSPHO1	ENST00000574638.1	c.*241G>C		downstream_gene_variant		3		ENSP00000461392.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.575G>C (p.S192T) alteration is located in exon 3 (coding exon 1) of the PHOSPHO1 gene. This alteration results from a G to C substitution at nucleotide position 575, causing the serine (S) at amino acid position 192 to be replaced by a threonine (T). 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	0.088
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	19
DANN	Benign	0.93
DEOGEN2	Benign	0.098	T;.;.;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.65	T;T;.;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.62	N;.;.;.
PhyloP100		0.46
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.2	N;N;N;N
REVEL	Benign	0.068
Sift	Benign	0.33	T;T;T;T
Sift4G	Benign	0.56	T;T;T;.
Polyphen		0.0060	B;.;.;.
Vest4		0.093
MutPred		0.52		Gain of catalytic residue at S167 (P = 0.0635);.;.;Gain of catalytic residue at S167 (P = 0.0635);
MVP		0.043
ClinPred		0.12	T
GERP RS		2.1
Varity_R		0.090
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

Other links and lift over

hg19: chr17-47301912;