1-42746756-G-C

Position:

• chr1-42746756-G-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_022356.4(P3H1):​c.2152C>G​(p.Pro718Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000371 in 1,555,520 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P718P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00038 (4 hom.)
• Consequence: P3H1 NM_022356.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 0.717

Genes affected

P3H1 (HGNC:19316): (prolyl 3-hydroxylase 1) This gene encodes an enzyme that is a member of the collagen prolyl hydroxylase family. These enzymes are localized to the endoplasmic reticulum and their activity is required for proper collagen synthesis and assembly. Mutations in this gene are associated with osteogenesis imperfecta type VIII. Three alternatively spliced transcript variants encoding different isoforms have been described. Other variants may exist, but their biological validity has not been determined. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031007528).
• BP6: Variant 1-42746756-G-C is Benign according to our data. Variant chr1-42746756-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194557.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000322 (49/152300) while in subpopulation EAS AF= 0.00889 (46/5176). AF 95% confidence interval is 0.00685. There are 0 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
P3H1	NM_022356.4	c.2152C>G	p.Pro718Ala	missense_variant	15/15	ENST00000296388.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
P3H1	ENST00000296388.10	c.2152C>G	p.Pro718Ala	missense_variant	15/15	1	NM_022356.4	P1

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 49 AN: 152182 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: 0.00887

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000859 AC: 140 AN: 162942 Hom.: 1 AF XY: 0.000660 AC XY: 57 AN XY: 86392

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000399

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0114

Gnomad SAS exome AF: 0.000171

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000155

Gnomad OTH exome AF: 0.000440

GnomAD4 exome AF: 0.000376 AC: 528 AN: 1403220 Hom.: 4 Cov.: 31 AF XY: 0.000355 AC XY: 246 AN XY: 692516

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000278

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0134

Gnomad4 SAS exome AF: 0.0000627

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000185

Gnomad4 OTH exome AF: 0.000361

GnomAD4 genome AF: 0.000322 AC: 49 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74464

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00889

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Bravo AF: 0.000438

ExAC AF: 0.000633 AC: 70

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 20, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 2021	- -

Osteogenesis imperfecta type 8 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

Osteogenesis Imperfecta, Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

P3H1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 21, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.3
DANN	Benign	0.70
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	N;N;N
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.046
Sift	Benign	0.11	T
Sift4G	Benign	0.83	T
Polyphen		0.10	B
Vest4		0.19
MutPred		0.096		Loss of glycosylation at P718 (P = 0.0164);
MVP		0.24
ClinPred		0.018	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.031

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

Publications

LitVar

Other links and lift over

dbSNP: rs533729683; hg19: chr1-43212427;