rs901833226

Variant names:

• chr17-49224401-C-A
• rs901833226
• NM_178500.4:c.649G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-49224401-C-A
• chr17-49224401-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_178500.4(PHOSPHO1):​c.649G>T​(p.Gly217Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000841 in 1,545,456 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 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000086 (0 hom.)
• Consequence: PHOSPHO1 NM_178500.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.541
• Publications: 1 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]

ACMG classification

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=0.35500538).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOSPHO1	NM_178500.4	c.649G>T	p.Gly217Cys	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.649G>T	p.Gly217Cys	missense_variant	Exon 3 of 3	2	NM_178500.4	ENSP00000311925.4
PHOSPHO1	ENST00000514112.1	c.724G>T	p.Gly242Cys	missense_variant	Exon 2 of 2	1		ENSP00000427694.1
PHOSPHO1	ENST00000413580.5	c.724G>T	p.Gly242Cys	missense_variant	Exon 3 of 3	2		ENSP00000406909.1
PHOSPHO1	ENST00000511066.5	c.*38G>T		downstream_gene_variant		2		ENSP00000426095.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152224 Hom.: 0 Cov.: 32

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000861 AC: 12 AN: 1393232 Hom.: 0 Cov.: 31 AF XY: 0.00000727 AC XY: 5 AN XY: 687896

African (AFR) AF: 0.00 AC: 0 AN: 31634

American (AMR) AF: 0.00 AC: 0 AN: 35874

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25136

East Asian (EAS) AF: 0.00 AC: 0 AN: 35812

South Asian (SAS) AF: 0.00 AC: 0 AN: 79744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41658

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5122

European-Non Finnish (NFE) AF: 0.0000111 AC: 12 AN: 1080354

Other (OTH) AF: 0.00 AC: 0 AN: 57898

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74366

African (AFR) AF: 0.00 AC: 0 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.724G>T (p.G242C) alteration is located in exon 3 (coding exon 1) of the PHOSPHO1 gene. This alteration results from a G to T substitution at nucleotide position 724, causing the glycine (G) at amino acid position 242 to be replaced by a cysteine (C). 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	0.12
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T;.;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.72	T;T;.
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.6	L;.;.
PhyloP100		0.54
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Benign	0.10
Sift	Uncertain	0.020	D;D;D
Sift4G	Benign	0.093	T;T;T
Polyphen		1.0	D;.;.
Vest4		0.17
MutPred		0.52		Loss of sheet (P = 0.1158);.;.;
MVP		0.043
ClinPred		0.97	D
GERP RS		4.5
Varity_R		0.26
gMVP		0.69
Mutation Taster		=82/18	polymorphism

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

dbSNP: rs901833226; hg19: chr17-47301763;