chr17-49224362-G-A

Variant names:

• chr17-49224362-G-A
• rs547226881
• NM_178500.4:c.688C>T

Variant summary

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

The NM_178500.4(PHOSPHO1):​c.688C>T​(p.Arg230Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000243 in 1,564,194 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R230S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: PHOSPHO1 NM_178500.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.44
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20191151).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOSPHO1	NM_178500.4	c.688C>T	p.Arg230Cys	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.688C>T	p.Arg230Cys	missense_variant	Exon 3 of 3	2	NM_178500.4	ENSP00000311925.4
PHOSPHO1	ENST00000514112.1	c.763C>T	p.Arg255Cys	missense_variant	Exon 2 of 2	1		ENSP00000427694.1
PHOSPHO1	ENST00000413580.5	c.763C>T	p.Arg255Cys	missense_variant	Exon 3 of 3	2		ENSP00000406909.1
PHOSPHO1	ENST00000511066.5	c.*77C>T		downstream_gene_variant		2		ENSP00000426095.1

Frequencies

GnomAD3 genomes AF: 0.0000525 AC: 8 AN: 152252 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

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: 0.0000818 AC: 13 AN: 159004 AF XY: 0.0000685

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000457

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000156

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 30 AN: 1411824 Hom.: 0 Cov.: 31 AF XY: 0.0000215 AC XY: 15 AN XY: 699122

African (AFR) AF: 0.0000309 AC: 1 AN: 32332

American (AMR) AF: 0.000739 AC: 28 AN: 37908

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25380

East Asian (EAS) AF: 0.00 AC: 0 AN: 36940

South Asian (SAS) AF: 0.00 AC: 0 AN: 81442

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5592

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1090262

Other (OTH) AF: 0.0000171 AC: 1 AN: 58638

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152370 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74506

African (AFR) AF: 0.00 AC: 0 AN: 41588

American (AMR) AF: 0.000522 AC: 8 AN: 15314

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

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

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000144

ExAC AF: 0.0000172 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.763C>T (p.R255C) 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 763, causing the arginine (R) at amino acid position 255 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	0.19
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;.;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;.
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.0	M;.;.
PhyloP100		4.4
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-5.2	D;D;D
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.45
MutPred		0.60		Gain of catalytic residue at M228 (P = 5e-04);.;.;
MVP		0.15
ClinPred		0.86	D
GERP RS		4.5
Varity_R		0.75
gMVP		0.73
Mutation Taster		=77/23	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: rs547226881; hg19: chr17-47301724;