chr17-49225109-A-G

Variant names:

• chr17-49225109-A-G
• rs1206487417
• ENST00000514112.1:c.16T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_178500.4(PHOSPHO1):​c.46-105T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000111 in 1,442,146 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: 0.000012 (0 hom.)
• Consequence: PHOSPHO1 NM_178500.4 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.21
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07586789).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOSPHO1	NM_178500.4	c.46-105T>C		intron_variant	Intron 2 of 2	ENST00000310544.9	NP_848595.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PHOSPHO1	ENST00000310544.9	c.46-105T>C		intron_variant	Intron 2 of 2	2	NM_178500.4	ENSP00000311925.4
PHOSPHO1	ENST00000574638.1	c.46-105T>C		intron_variant	Intron 2 of 2	3		ENSP00000461392.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152256 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000146 AC: 9 AN: 61444 AF XY: 0.0000972

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000757

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000126

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 15 AN: 1289890 Hom.: 0 Cov.: 31 AF XY: 0.0000112 AC XY: 7 AN XY: 626432

African (AFR) AF: 0.00 AC: 0 AN: 28266

American (AMR) AF: 0.000507 AC: 10 AN: 19714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18900

East Asian (EAS) AF: 0.0000286 AC: 1 AN: 34964

South Asian (SAS) AF: 0.00 AC: 0 AN: 63194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30528

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4736

European-Non Finnish (NFE) AF: 9.65e-7 AC: 1 AN: 1035912

Other (OTH) AF: 0.0000559 AC: 3 AN: 53676

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74380

African (AFR) AF: 0.00 AC: 0 AN: 41476

American (AMR) AF: 0.0000654 AC: 1 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.16T>C (p.W6R) alteration is located in exon 3 (coding exon 1) of the PHOSPHO1 gene. This alteration results from a T to C substitution at nucleotide position 16, causing the tryptophan (W) at amino acid position 6 to be replaced by an arginine (R). 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
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Uncertain	0.97
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.27	T;.;T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.076	T;T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		1.2
PROVEAN	Benign	-0.67	N;N;N;N
REVEL	Benign	0.054
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;.;.
Vest4		0.37
MutPred		0.25		Loss of catalytic residue at P9 (P = 0.0506);Loss of catalytic residue at P9 (P = 0.0506);Loss of catalytic residue at P9 (P = 0.0506);.;
MVP		0.043
ClinPred		0.19	T
GERP RS		3.9
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1206487417; hg19: chr17-47302471;