chr17-49224493-C-T

Variant names:

• chr17-49224493-C-T
• rs569600565
• NM_178500.4:c.557G>A

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.557G>A​(p.Arg186His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000305 in 1,571,656 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 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000032 (0 hom.)
• Consequence: PHOSPHO1 NM_178500.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.25
• 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]

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=0.23266804).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOSPHO1	NM_178500.4	c.557G>A	p.Arg186His	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.557G>A	p.Arg186His	missense_variant	Exon 3 of 3	2	NM_178500.4	ENSP00000311925.4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152258 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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000167 AC: 3 AN: 179564 AF XY: 0.0000203

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000399

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000317 AC: 45 AN: 1419398 Hom.: 0 Cov.: 31 AF XY: 0.0000384 AC XY: 27 AN XY: 702840

African (AFR) AF: 0.00 AC: 0 AN: 32406

American (AMR) AF: 0.00 AC: 0 AN: 39188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25422

East Asian (EAS) AF: 0.00 AC: 0 AN: 37210

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 81704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4822

European-Non Finnish (NFE) AF: 0.0000402 AC: 44 AN: 1093284

Other (OTH) AF: 0.00 AC: 0 AN: 58764

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74392

African (AFR) AF: 0.00 AC: 0 AN: 41474

American (AMR) AF: 0.00 AC: 0 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000841 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.632G>A (p.R211H) alteration is located in exon 3 (coding exon 1) of the PHOSPHO1 gene. This alteration results from a G to A substitution at nucleotide position 632, causing the arginine (R) at amino acid position 211 to be replaced by a histidine (H). 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	0.094
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;.;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.91	D;D;.;D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.7	L;.;.;.
PhyloP100		2.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.2	N;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.11	T;T;T;T
Sift4G	Benign	0.11	T;T;T;.
Polyphen		0.98	D;.;.;.
Vest4		0.13
MutPred		0.57		Gain of phosphorylation at Y184 (P = 0.1558);.;.;Gain of phosphorylation at Y184 (P = 0.1558);
MVP		0.068
ClinPred		0.73	D
GERP RS		4.2
Varity_R		0.062
gMVP		0.59
Mutation Taster		=89/11	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: rs569600565; hg19: chr17-47301855;