rs6882

Variant names:

• chr1-42746440-C-T
• rs6882
• NM_022356.4:c.*257G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 11 publications found

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]

P3H1 Gene-Disease associations (from GenCC):

• osteogenesis imperfecta type 8

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• osteogenesis imperfecta type 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• osteogenesis imperfecta type 3

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• 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 rank	MANE	Protein	UniProt
P3H1	NM_022356.4	c.*257G>A		3_prime_UTR_variant	Exon 15 of 15	ENST00000296388.10	NP_071751.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P3H1	ENST00000296388.10	c.*257G>A		3_prime_UTR_variant	Exon 15 of 15	1	NM_022356.4	ENSP00000296388.5

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

African (AFR) AF: 0.557 AC: 6585 AN: 11818

American (AMR) AF: 0.659 AC: 11334 AN: 17198

Ashkenazi Jewish (ASJ) AF: 0.661 AC: 8405 AN: 12722

East Asian (EAS) AF: 0.654 AC: 18752 AN: 28692

South Asian (SAS) AF: 0.781 AC: 29748 AN: 38072

European-Finnish (FIN) AF: 0.667 AC: 17991 AN: 26986

Middle Eastern (MID) AF: 0.661 AC: 1209 AN: 1828

European-Non Finnish (NFE) AF: 0.672 AC: 163716 AN: 243714

Other (OTH) AF: 0.663 AC: 15872 AN: 23946

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

African (AFR) AF: 0.556 AC: 23056 AN: 41498

American (AMR) AF: 0.652 AC: 9977 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.662 AC: 2298 AN: 3470

East Asian (EAS) AF: 0.708 AC: 3666 AN: 5178

South Asian (SAS) AF: 0.775 AC: 3744 AN: 4832

European-Finnish (FIN) AF: 0.653 AC: 6915 AN: 10592

Middle Eastern (MID) AF: 0.653 AC: 192 AN: 294

European-Non Finnish (NFE) AF: 0.675 AC: 45937 AN: 68010

Other (OTH) AF: 0.641 AC: 1357 AN: 2116

Alfa AF: 0.661 Hom.: 42265

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

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:2

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Osteogenesis Imperfecta, Recessive Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs6882; hg19: chr1-43212111;