1-42746686-CCTGGACG-C

Variant names:

• chr1-42746686-CCTGGACG-C
• rs767524042
• NM_022356.4:c.*4_*10delCGTCCAG

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_022356.4(P3H1):​c.*4_*10delCGTCCAG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 1,549,480 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: P3H1 NM_022356.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.315
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 1-42746686-CCTGGACG-C is Benign according to our data. Variant chr1-42746686-CCTGGACG-C is described in ClinVar as [Likely_benign]. Clinvar id is 421364.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P3H1	NM_022356.4	c.*4_*10delCGTCCAG		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.*4_*10delCGTCCAG		3_prime_UTR_variant	Exon 15 of 15	1	NM_022356.4	ENSP00000296388.5

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152210 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: 0.000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000123 AC: 19 AN: 154136 AF XY: 0.000122

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000270

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000132 AC: 184 AN: 1397152 Hom.: 1 AF XY: 0.000138 AC XY: 95 AN XY: 689252

African (AFR) AF: 0.00 AC: 0 AN: 31556

American (AMR) AF: 0.000140 AC: 5 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.0000397 AC: 1 AN: 25174

East Asian (EAS) AF: 0.00 AC: 0 AN: 35734

South Asian (SAS) AF: 0.00 AC: 0 AN: 79200

European-Finnish (FIN) AF: 0.0000407 AC: 2 AN: 49196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5654

European-Non Finnish (NFE) AF: 0.000159 AC: 171 AN: 1076992

Other (OTH) AF: 0.0000863 AC: 5 AN: 57944

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152328 Hom.: 0 Cov.: 32 AF XY: 0.0000268 AC XY: 2 AN XY: 74488

African (AFR) AF: 0.00 AC: 0 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000304 Hom.: 0

Bravo AF: 0.000102

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jun 06, 2016

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.32
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs767524042; hg19: chr1-43212357;