rs61746642

Variant names:

• chr1-42754930-G-A
• rs61746642
• NM_022356.4:c.1284C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-42754930-G-A
• chr1-42754930-G-C

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.1284C>T​(p.Ile428Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00291 in 1,614,110 control chromosomes in the GnomAD database, including 115 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 (62 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (53 hom.)
• Consequence: P3H1 NM_022356.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -1.29
• Publications: 2 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=-0.59).
• BP6: Variant 1-42754930-G-A is Benign according to our data. Variant chr1-42754930-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 379769.
• BP7: Synonymous conserved (PhyloP=-1.29 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.1284C>T	p.Ile428Ile	synonymous	Exon 8 of 15	NP_071751.3
	P3H1	NM_001243246.2		c.1284C>T	p.Ile428Ile	synonymous	Exon 8 of 14	NP_001230175.1	Q32P28-3
	P3H1	NM_001146289.2		c.1284C>T	p.Ile428Ile	synonymous	Exon 8 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.1284C>T	p.Ile428Ile	synonymous	Exon 8 of 15	ENSP00000296388.5	Q32P28-1
	P3H1	ENST00000397054.7	TSL:1	c.1284C>T	p.Ile428Ile	synonymous	Exon 8 of 15	ENSP00000380245.3	Q32P28-4
	P3H1	ENST00000907902.1		c.1608C>T	p.Ile536Ile	synonymous	Exon 8 of 15	ENSP00000577961.1

Frequencies

GnomAD3 genomes AF: 0.0147 AC: 2240 AN: 152116 Hom.: 62 Cov.: 32

Gnomad AFR AF: 0.0506

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: 0.000397

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00407 AC: 1024 AN: 251460 AF XY: 0.00315

Gnomad AFR exome AF: 0.0520

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: 0.000519

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00167 AC: 2447 AN: 1461876 Hom.: 53 Cov.: 32 AF XY: 0.00145 AC XY: 1051 AN XY: 727238

African (AFR) AF: 0.0532 AC: 1780 AN: 33480

American (AMR) AF: 0.00349 AC: 156 AN: 44724

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

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

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.000249 AC: 277 AN: 1112000

Other (OTH) AF: 0.00353 AC: 213 AN: 60396

GnomAD4 genome AF: 0.0147 AC: 2243 AN: 152234 Hom.: 62 Cov.: 32 AF XY: 0.0145 AC XY: 1079 AN XY: 74442

African (AFR) AF: 0.0505 AC: 2098 AN: 41522

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: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68004

Other (OTH) AF: 0.00805 AC: 17 AN: 2112

Alfa AF: 0.00691 Hom.: 12

Bravo AF: 0.0167

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000356

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	-0.59
CADD	Benign	4.0
DANN	Benign	0.85
PhyloP100		-1.3
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: rs61746642; hg19: chr1-43220601; COSMIC: COSV52537101; COSMIC: COSV52537101;