17-49225115-G-C

Variant names:

• chr17-49225115-G-C
• rs1277427387
• ENST00000514112.1:c.10C>G

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.46-111C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000763 in 1,441,232 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: 0.0000078 (0 hom.)
• Consequence: PHOSPHO1 NM_178500.4 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.08
• 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: 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=0.0803383).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PHOSPHO1	NM_178500.4	c.46-111C>G		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.46-111C>G		intron_variant	Intron 2 of 2	2	NM_178500.4	ENSP00000311925.4
PHOSPHO1	ENST00000574638.1	c.46-111C>G		intron_variant	Intron 2 of 2	3		ENSP00000461392.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152232 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: 0.00000776 AC: 10 AN: 1289000 Hom.: 0 Cov.: 31 AF XY: 0.00000479 AC XY: 3 AN XY: 625770

African (AFR) AF: 0.00 AC: 0 AN: 28256

American (AMR) AF: 0.00 AC: 0 AN: 19696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18886

East Asian (EAS) AF: 0.00 AC: 0 AN: 34932

South Asian (SAS) AF: 0.00 AC: 0 AN: 63106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30474

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4692

European-Non Finnish (NFE) AF: 0.00000869 AC: 9 AN: 1035310

Other (OTH) AF: 0.0000186 AC: 1 AN: 53648

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152232 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74366

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15288

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: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.10C>G (p.R4G) alteration is located in exon 3 (coding exon 1) of the PHOSPHO1 gene. This alteration results from a C to G substitution at nucleotide position 10, causing the arginine (R) at amino acid position 4 to be replaced by a glycine (G). 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	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	17
DANN	Uncertain	0.98
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.46	T;.;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.080	T;T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		1.1
PROVEAN	Benign	-0.31	N;N;N;N
REVEL	Benign	0.031
Sift	Uncertain	0.016	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;.;.
Vest4		0.38
MutPred		0.23		Loss of MoRF binding (P = 0.0011);Loss of MoRF binding (P = 0.0011);Loss of MoRF binding (P = 0.0011);.;
MVP		0.043
ClinPred		0.13	T
GERP RS		3.1
gMVP		0.46

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: rs1277427387; hg19: chr17-47302477;