1-42746440-C-T

Position:

• chr1-42746440-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022356.4(P3H1):​c.*257G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.666 in 557,178 control chromosomes in the GnomAD database, including 124,843 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.64 (31661 hom., cov: 34)
  • Exomes 𝑓: 0.68 (93182 hom.)
• Consequence: P3H1 NM_022356.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.225

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 1-42746440-C-T is Benign according to our data. Variant chr1-42746440-C-T is described in ClinVar as [Benign]. Clinvar id is 873598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.754 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
P3H1	NM_022356.4	c.*257G>A		3_prime_UTR_variant	15/15	ENST00000296388.10	NP_071751.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
P3H1	ENST00000296388.10	c.*257G>A		3_prime_UTR_variant	15/15	1	NM_022356.4	ENSP00000296388	P1

Frequencies

GnomAD3 genomes AF: 0.642 AC: 97670 AN: 152084 Hom.: 31658 Cov.: 34

Gnomad AFR AF: 0.556

Gnomad AMI AF: 0.620

Gnomad AMR AF: 0.652

Gnomad ASJ AF: 0.662

Gnomad EAS AF: 0.708

Gnomad SAS AF: 0.775

Gnomad FIN AF: 0.653

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.675

Gnomad OTH AF: 0.642

GnomAD4 exome AF: 0.676 AC: 273612 AN: 404976 Hom.: 93182 Cov.: 2 AF XY: 0.682 AC XY: 143909 AN XY: 211116

Gnomad4 AFR exome AF: 0.557

Gnomad4 AMR exome AF: 0.659

Gnomad4 ASJ exome AF: 0.661

Gnomad4 EAS exome AF: 0.654

Gnomad4 SAS exome AF: 0.781

Gnomad4 FIN exome AF: 0.667

Gnomad4 NFE exome AF: 0.672

Gnomad4 OTH exome AF: 0.663

GnomAD4 genome AF: 0.642 AC: 97706 AN: 152202 Hom.: 31661 Cov.: 34 AF XY: 0.644 AC XY: 47919 AN XY: 74414

Gnomad4 AFR AF: 0.556

Gnomad4 AMR AF: 0.652

Gnomad4 ASJ AF: 0.662

Gnomad4 EAS AF: 0.708

Gnomad4 SAS AF: 0.775

Gnomad4 FIN AF: 0.653

Gnomad4 NFE AF: 0.675

Gnomad4 OTH AF: 0.641

Alfa AF: 0.665 Hom.: 32656

Bravo AF: 0.637

Asia WGS AF: 0.736 AC: 2559 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Osteogenesis imperfecta type 8 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Osteogenesis Imperfecta, Recessive Benign:1

Benign, 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.4
DANN	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs6882; hg19: chr1-43212111;