1-42752314-T-C

Variant names:

• chr1-42752314-T-C
• rs149894086
• NM_022356.4:c.1529A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_022356.4(P3H1):​c.1529A>G​(p.Asn510Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000171 in 1,614,108 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N510T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00089 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000096 (1 hom.)
• Consequence: P3H1 NM_022356.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.257
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007150173).
• BP6: Variant 1-42752314-T-C is Benign according to our data. Variant chr1-42752314-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 289042.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000893 (136/152266) while in subpopulation AFR AF = 0.00325 (135/41542). AF 95% confidence interval is 0.0028. There are 1 homozygotes in GnomAd4. There are 64 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.1529A>G	p.Asn510Ser	missense	Exon 10 of 15	NP_071751.3
	P3H1	NM_001243246.2		c.1529A>G	p.Asn510Ser	missense	Exon 10 of 14	NP_001230175.1	Q32P28-3
	P3H1	NM_001146289.2		c.1529A>G	p.Asn510Ser	missense	Exon 10 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.1529A>G	p.Asn510Ser	missense	Exon 10 of 15	ENSP00000296388.5	Q32P28-1
	P3H1	ENST00000397054.7	TSL:1	c.1529A>G	p.Asn510Ser	missense	Exon 10 of 15	ENSP00000380245.3	Q32P28-4
	P3H1	ENST00000907902.1		c.1853A>G	p.Asn618Ser	missense	Exon 10 of 15	ENSP00000577961.1

Frequencies

GnomAD3 genomes AF: 0.000894 AC: 136 AN: 152148 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000251 AC: 63 AN: 251472 AF XY: 0.000191

Gnomad AFR exome AF: 0.00314

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000958 AC: 140 AN: 1461842 Hom.: 1 Cov.: 32 AF XY: 0.0000866 AC XY: 63 AN XY: 727230

African (AFR) AF: 0.00308 AC: 103 AN: 33480

American (AMR) AF: 0.000179 AC: 8 AN: 44722

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1111980

Other (OTH) AF: 0.000116 AC: 7 AN: 60396

GnomAD4 genome AF: 0.000893 AC: 136 AN: 152266 Hom.: 1 Cov.: 32 AF XY: 0.000859 AC XY: 64 AN XY: 74470

African (AFR) AF: 0.00325 AC: 135 AN: 41542

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2104

Alfa AF: 0.000310 Hom.: 0

Bravo AF: 0.000918

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000329 AC: 40

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	not specified (1)
-	-	1	Osteogenesis imperfecta type 8 (1)
-	-	1	P3H1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	8.3
DANN	Benign	0.93
DEOGEN2	Benign	0.18	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.29	N
PhyloP100		0.26
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.023
Sift	Benign	0.28	T
Sift4G	Benign	0.46	T
Polyphen		0.0030	B
Vest4		0.053
MVP		0.17
MPC		0.15
ClinPred		0.0023	T
GERP RS		-3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.028
gMVP		0.21
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs149894086; hg19: chr1-43217985;