chr17-49225022-A-G

Position:

• chr17-49225022-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000514112.1(PHOSPHO1):​c.103T>C​(p.Ser35Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000735 in 1,333,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/16 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)
  • Exomes 𝑓: 0.000073 (0 hom.)
• Consequence: PHOSPHO1 ENST00000514112.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.230

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.044225782).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHOSPHO1	NM_178500.4	c.46-18T>C		intron_variant		ENST00000310544.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHOSPHO1	ENST00000310544.9	c.46-18T>C		intron_variant		2	NM_178500.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000735 AC: 98 AN: 1333578 Hom.: 0 Cov.: 31 AF XY: 0.0000829 AC XY: 54 AN XY: 651526

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000274

Gnomad4 NFE exome AF: 0.0000904

Gnomad4 OTH exome AF: 0.0000361

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2022

The c.103T>C (p.S35P) 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 103, causing the serine (S) at amino acid position 35 to be replaced by a proline (P). 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	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	15
DANN	Benign	0.92
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.091	N
LIST_S2	Benign	0.27	T;.;T;T
M_CAP	Benign	0.0032	T
MetaRNN	Benign	0.044	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PROVEAN	Benign	-0.020	N;N;N;N
REVEL	Benign	0.037
Sift	Benign	0.17	T;T;T;D
Sift4G	Benign	0.22	T;T;.;.
Vest4		0.17
MutPred		0.15		Loss of phosphorylation at S35 (P = 0.0294);Loss of phosphorylation at S35 (P = 0.0294);Loss of phosphorylation at S35 (P = 0.0294);.;
MVP		0.068
ClinPred		0.044	T
GERP RS		1.5
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1177206487; hg19: chr17-47302384;