chr1-42752271-T-C

Variant names:

• chr1-42752271-T-C
• rs76871760
• NM_022356.4:c.1569+3A>G

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.1569+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00277 in 1,611,898 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.015 (62 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (52 hom.)
• Consequence: P3H1 NM_022356.4 splice_region, intron
• Scores: Splicing: ADA: 0.08602
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 1.13
• 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: 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 1-42752271-T-C is Benign according to our data. Variant chr1-42752271-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 379770.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0509 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.1569+3A>G		splice_region intron	N/A	NP_071751.3
	P3H1	NM_001243246.2		c.1569+3A>G		splice_region intron	N/A	NP_001230175.1	Q32P28-3
	P3H1	NM_001146289.2		c.1569+3A>G		splice_region intron	N/A	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.1569+3A>G		splice_region intron	N/A	ENSP00000296388.5	Q32P28-1
	P3H1	ENST00000397054.7	TSL:1	c.1569+3A>G		splice_region intron	N/A	ENSP00000380245.3	Q32P28-4
	P3H1	ENST00000907902.1		c.1893+3A>G		splice_region intron	N/A	ENSP00000577961.1

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2220 AN: 151998 Hom.: 62 Cov.: 32

Gnomad AFR AF: 0.0505

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00642

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: 0.000221

Gnomad OTH AF: 0.00815

GnomAD2 exomes AF: 0.00396 AC: 995 AN: 251432 AF XY: 0.00304

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: 0.000272

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00154 AC: 2246 AN: 1459782 Hom.: 52 Cov.: 31 AF XY: 0.00131 AC XY: 953 AN XY: 726354

African (AFR) AF: 0.0530 AC: 1769 AN: 33404

American (AMR) AF: 0.00349 AC: 156 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5766

European-Non Finnish (NFE) AF: 0.0000856 AC: 95 AN: 1110162

Other (OTH) AF: 0.00346 AC: 209 AN: 60340

GnomAD4 genome AF: 0.0146 AC: 2224 AN: 152116 Hom.: 62 Cov.: 32 AF XY: 0.0144 AC XY: 1070 AN XY: 74364

African (AFR) AF: 0.0505 AC: 2092 AN: 41466

American (AMR) AF: 0.00634 AC: 97 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67966

Other (OTH) AF: 0.00806 AC: 17 AN: 2108

Alfa AF: 0.00823 Hom.: 19

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)
-	-	2	not specified (2)
-	-	1	Osteogenesis imperfecta (1)
-	1	-	Osteogenesis Imperfecta, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	19
DANN	Benign	0.81
PhyloP100		1.1
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.086
dbscSNV1_RF	Benign	0.27
Splicevardb		2.0
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: rs76871760; hg19: chr1-43217942;