rs55716016

Variant names:

• chr1-42766833-C-A
• rs55716016
• NM_022356.4:c.139G>T

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.139G>T​(p.Ala47Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0327 in 1,604,686 control chromosomes in the GnomAD database, including 1,076 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. A47A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.041 (193 hom., cov: 33)
  • Exomes 𝑓: 0.032 (883 hom.)
• Consequence: P3H1 NM_022356.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.206
• Publications: 8 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 (MetaRNN=0.0025526285).
• BP6: Variant 1-42766833-C-A is Benign according to our data. Variant chr1-42766833-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 379443.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0735 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.139G>T	p.Ala47Ser	missense	Exon 1 of 15	NP_071751.3
	P3H1	NM_001243246.2		c.139G>T	p.Ala47Ser	missense	Exon 1 of 14	NP_001230175.1	Q32P28-3
	P3H1	NM_001146289.2		c.139G>T	p.Ala47Ser	missense	Exon 1 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.139G>T	p.Ala47Ser	missense	Exon 1 of 15	ENSP00000296388.5	Q32P28-1
	P3H1	ENST00000397054.7	TSL:1	c.139G>T	p.Ala47Ser	missense	Exon 1 of 15	ENSP00000380245.3	Q32P28-4
	P3H1	ENST00000492956.1	TSL:1	n.185G>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.0414 AC: 6297 AN: 152182 Hom.: 192 Cov.: 33

Gnomad AFR AF: 0.0756

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.0249

Gnomad ASJ AF: 0.0389

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0437

Gnomad FIN AF: 0.0210

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0296

Gnomad OTH AF: 0.0521

GnomAD2 exomes AF: 0.0311 AC: 7174 AN: 230808 AF XY: 0.0320

Gnomad AFR exome AF: 0.0806

Gnomad AMR exome AF: 0.0216

Gnomad ASJ exome AF: 0.0392

Gnomad EAS exome AF: 0.00181

Gnomad FIN exome AF: 0.0179

Gnomad NFE exome AF: 0.0295

Gnomad OTH exome AF: 0.0320

GnomAD4 exome AF: 0.0318 AC: 46129 AN: 1452386 Hom.: 883 Cov.: 32 AF XY: 0.0320 AC XY: 23119 AN XY: 722992

African (AFR) AF: 0.0836 AC: 2796 AN: 33464

American (AMR) AF: 0.0234 AC: 1045 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.0391 AC: 1021 AN: 26098

East Asian (EAS) AF: 0.000781 AC: 31 AN: 39684

South Asian (SAS) AF: 0.0442 AC: 3811 AN: 86244

European-Finnish (FIN) AF: 0.0178 AC: 792 AN: 44430

Middle Eastern (MID) AF: 0.0411 AC: 237 AN: 5768

European-Non Finnish (NFE) AF: 0.0310 AC: 34471 AN: 1111718

Other (OTH) AF: 0.0319 AC: 1925 AN: 60292

GnomAD4 genome AF: 0.0414 AC: 6309 AN: 152300 Hom.: 193 Cov.: 33 AF XY: 0.0408 AC XY: 3035 AN XY: 74478

African (AFR) AF: 0.0757 AC: 3146 AN: 41570

American (AMR) AF: 0.0249 AC: 381 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0389 AC: 135 AN: 3468

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5176

South Asian (SAS) AF: 0.0439 AC: 212 AN: 4828

European-Finnish (FIN) AF: 0.0210 AC: 223 AN: 10616

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0296 AC: 2010 AN: 68012

Other (OTH) AF: 0.0510 AC: 108 AN: 2116

Alfa AF: 0.0319 Hom.: 292

Bravo AF: 0.0432

TwinsUK AF: 0.0310 AC: 115

ALSPAC AF: 0.0358 AC: 138

ESP6500AA AF: 0.0676 AC: 276

ESP6500EA AF: 0.0297 AC: 243

ExAC AF: 0.0306 AC: 3643

Asia WGS AF: 0.0190 AC: 67 AN: 3478

EpiCase AF: 0.0357

EpiControl AF: 0.0339

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	Osteogenesis imperfecta type 8 (4)
-	-	1	not specified (1)
-	-	1	Osteogenesis imperfecta (1)
-	1	-	Osteogenesis Imperfecta, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.064	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.21
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.014
Sift	Benign	0.39	T
Sift4G	Benign	0.38	T
Polyphen		0.047	B
Vest4		0.090
MPC		0.94
ClinPred		0.019	T
GERP RS		3.2
PromoterAI		0.018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.052
gMVP		0.52
Mutation Taster		=99/1	polymorphism (auto)

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: rs55716016; hg19: chr1-43232504;