rs149113630

chr1-42759316-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The NM_022356.4(P3H1):c.693G>A(p.Ala231=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000564 in 1,614,182 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. A231A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00060 (1 hom.)
• Consequence: P3H1 NM_022356.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -4.26

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 1-42759316-C-T is Benign according to our data. Variant chr1-42759316-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 468988.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}. Variant chr1-42759316-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-4.26 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
P3H1	NM_022356.4	c.693G>A	p.Ala231=	synonymous_variant	3/15	ENST00000296388.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
P3H1	ENST00000296388.10	c.693G>A	p.Ala231=	synonymous_variant	3/15	1	NM_022356.4	P1

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000412

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000215 AC: 54 AN: 251464 Hom.: 0 AF XY: 0.000221 AC XY: 30 AN XY: 135898

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000431

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000598 AC: 874 AN: 1461888 Hom.: 1 Cov.: 32 AF XY: 0.000601 AC XY: 437 AN XY: 727248

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.000754

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000236 AC: 36 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.000201 AC XY: 15 AN XY: 74472

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000474 Hom.: 0

Bravo AF: 0.000261

EpiCase AF: 0.000382

EpiControl AF: 0.000356

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

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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 18, 2017

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. -

Osteogenesis imperfecta type 8 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	2.8
Dann	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs149113630; hg19: chr1-43224987;