1-42746620-G-A

Variant names:

• chr1-42746620-G-A
• rs13871
• NM_022356.4:c.*77C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_022356.4(P3H1):​c.*77C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0454 in 1,253,560 control chromosomes in the GnomAD database, including 1,611 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.059 (360 hom., cov: 33)
  • Exomes 𝑓: 0.044 (1251 hom.)
• Consequence: P3H1 NM_022356.4 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -1.25
• Publications: 9 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 1-42746620-G-A is Benign according to our data. Variant chr1-42746620-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 873600.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P3H1	NM_022356.4	c.*77C>T		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.*77C>T		3_prime_UTR_variant	Exon 15 of 15	1	NM_022356.4	ENSP00000296388.5

Frequencies

GnomAD3 genomes AF: 0.0587 AC: 8928 AN: 152082 Hom.: 358 Cov.: 33

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.0469

Gnomad ASJ AF: 0.0605

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0557

Gnomad FIN AF: 0.0308

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0409

Gnomad OTH AF: 0.0686

GnomAD4 exome AF: 0.0436 AC: 47990 AN: 1101360 Hom.: 1251 Cov.: 15 AF XY: 0.0438 AC XY: 24331 AN XY: 555120

African (AFR) AF: 0.116 AC: 2965 AN: 25644

American (AMR) AF: 0.0412 AC: 1447 AN: 35148

Ashkenazi Jewish (ASJ) AF: 0.0608 AC: 1409 AN: 23156

East Asian (EAS) AF: 0.000641 AC: 22 AN: 34348

South Asian (SAS) AF: 0.0545 AC: 3990 AN: 73174

European-Finnish (FIN) AF: 0.0280 AC: 1354 AN: 48398

Middle Eastern (MID) AF: 0.0708 AC: 272 AN: 3842

European-Non Finnish (NFE) AF: 0.0423 AC: 34241 AN: 809686

Other (OTH) AF: 0.0477 AC: 2290 AN: 47964

GnomAD4 genome AF: 0.0588 AC: 8944 AN: 152200 Hom.: 360 Cov.: 33 AF XY: 0.0578 AC XY: 4303 AN XY: 74406

African (AFR) AF: 0.106 AC: 4400 AN: 41520

American (AMR) AF: 0.0468 AC: 716 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0605 AC: 210 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5168

South Asian (SAS) AF: 0.0558 AC: 269 AN: 4822

European-Finnish (FIN) AF: 0.0308 AC: 327 AN: 10612

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0408 AC: 2777 AN: 68000

Other (OTH) AF: 0.0678 AC: 143 AN: 2108

Alfa AF: 0.0498 Hom.: 98

Bravo AF: 0.0634

Asia WGS AF: 0.0270 AC: 93 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Osteogenesis Imperfecta, Recessive Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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 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. -

Osteogenesis imperfecta type 8 Benign:1

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:1

Jun 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.6
DANN	Benign	0.58
PhyloP100		-1.2
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: rs13871; hg19: chr1-43212291;