chr1-42754981-C-T

Variant names:

• chr1-42754981-C-T
• rs61746653
• NM_022356.4:c.1233G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4 BP6 BP7 BS1 BS2

The NM_022356.4(P3H1):​c.1233G>A​(p.Arg411Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,614,204 control chromosomes in the GnomAD database, including 58 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 0.010 (30 hom., cov: 32)
  • Exomes 𝑓: 0.00096 (28 hom.)
• Consequence: P3H1 NM_022356.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.634
• 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.288).
• BP6: Variant 1-42754981-C-T is Benign according to our data. Variant chr1-42754981-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 379643.
• BP7: Synonymous conserved (PhyloP=0.634 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.01 (1528/152328) while in subpopulation AFR AF = 0.0354 (1473/41572). AF 95% confidence interval is 0.0339. There are 30 homozygotes in GnomAd4. There are 745 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 30 AD,AR gene

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.1233G>A	p.Arg411Arg	synonymous	Exon 8 of 15	NP_071751.3
	P3H1	NM_001243246.2		c.1233G>A	p.Arg411Arg	synonymous	Exon 8 of 14	NP_001230175.1	Q32P28-3
	P3H1	NM_001146289.2		c.1233G>A	p.Arg411Arg	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.1233G>A	p.Arg411Arg	synonymous	Exon 8 of 15	ENSP00000296388.5	Q32P28-1
	P3H1	ENST00000397054.7	TSL:1	c.1233G>A	p.Arg411Arg	synonymous	Exon 8 of 15	ENSP00000380245.3	Q32P28-4
	P3H1	ENST00000907902.1		c.1557G>A	p.Arg519Arg	synonymous	Exon 8 of 15	ENSP00000577961.1

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1522 AN: 152210 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.0354

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

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: 0.000132

Gnomad OTH AF: 0.00669

GnomAD2 exomes AF: 0.00260 AC: 654 AN: 251438 AF XY: 0.00189

Gnomad AFR exome AF: 0.0367

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000959 AC: 1402 AN: 1461876 Hom.: 28 Cov.: 33 AF XY: 0.000825 AC XY: 600 AN XY: 727234

African (AFR) AF: 0.0346 AC: 1158 AN: 33480

American (AMR) AF: 0.00152 AC: 68 AN: 44722

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1112010

Other (OTH) AF: 0.00237 AC: 143 AN: 60396

GnomAD4 genome AF: 0.0100 AC: 1528 AN: 152328 Hom.: 30 Cov.: 32 AF XY: 0.0100 AC XY: 745 AN XY: 74490

African (AFR) AF: 0.0354 AC: 1473 AN: 41572

American (AMR) AF: 0.00209 AC: 32 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68032

Other (OTH) AF: 0.00662 AC: 14 AN: 2114

Alfa AF: 0.00504 Hom.: 5

Bravo AF: 0.0116

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

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	-0.27
CADD	Benign	10
DANN	Benign	0.86
PhyloP100		0.63
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61746653; hg19: chr1-43220652; COSMIC: COSV104581967; COSMIC: COSV104581967;