chr1-42748226-G-A

Variant names:

• chr1-42748226-G-A
• rs34809608
• NM_022356.4:c.1812C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_022356.4(P3H1):​c.1812C>T​(p.Pro604Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00278 in 1,613,822 control chromosomes in the GnomAD database, including 113 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 0.015 (61 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (52 hom.)
• Consequence: P3H1 NM_022356.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.112
• Publications: 1 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: G2P, Labcorp Genetics (formerly Invitae)
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 1-42748226-G-A is Benign according to our data. Variant chr1-42748226-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 379771.
• BP7: Synonymous conserved (PhyloP=-0.112 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0511 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022356.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P3H1	NM_022356.4	MANE Select	c.1812C>T	p.Pro604Pro	synonymous	Exon 12 of 15	NP_071751.3
	P3H1	NM_001243246.2		c.1812C>T	p.Pro604Pro	synonymous	Exon 12 of 14	NP_001230175.1	Q32P28-3
	P3H1	NM_001146289.2		c.1812C>T	p.Pro604Pro	synonymous	Exon 12 of 15	NP_001139761.1	Q32P28-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P3H1	ENST00000296388.10	TSL:1 MANE Select	c.1812C>T	p.Pro604Pro	synonymous	Exon 12 of 15	ENSP00000296388.5	Q32P28-1
	P3H1	ENST00000397054.7	TSL:1	c.1812C>T	p.Pro604Pro	synonymous	Exon 12 of 15	ENSP00000380245.3	Q32P28-4
	P3H1	ENST00000907902.1		c.2136C>T	p.Pro712Pro	synonymous	Exon 12 of 15	ENSP00000577961.1

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2219 AN: 152086 Hom.: 61 Cov.: 32

Gnomad AFR AF: 0.0504

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00648

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00817

GnomAD2 exomes AF: 0.00396 AC: 994 AN: 251014 AF XY: 0.00303

Gnomad AFR exome AF: 0.0519

Gnomad AMR exome AF: 0.00318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00154 AC: 2256 AN: 1461618 Hom.: 52 Cov.: 31 AF XY: 0.00132 AC XY: 957 AN XY: 727132

African (AFR) AF: 0.0531 AC: 1778 AN: 33480

American (AMR) AF: 0.00349 AC: 156 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53220

Middle Eastern (MID) AF: 0.00260 AC: 15 AN: 5768

European-Non Finnish (NFE) AF: 0.0000845 AC: 94 AN: 1111946

Other (OTH) AF: 0.00346 AC: 209 AN: 60390

GnomAD4 genome AF: 0.0146 AC: 2223 AN: 152204 Hom.: 61 Cov.: 32 AF XY: 0.0144 AC XY: 1070 AN XY: 74406

African (AFR) AF: 0.0504 AC: 2091 AN: 41504

American (AMR) AF: 0.00641 AC: 98 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68020

Other (OTH) AF: 0.00808 AC: 17 AN: 2104

Alfa AF: 0.00637 Hom.: 13

Bravo AF: 0.0166

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	Osteogenesis imperfecta type 8 (3)
-	-	1	not specified (1)
-	-	1	Osteogenesis imperfecta (1)
-	1	-	Osteogenesis Imperfecta, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	7.5
DANN	Benign	0.59
PhyloP100		-0.11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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: rs34809608; hg19: chr1-43213897;