chr1-42747797-C-A

Variant names:

• chr1-42747797-C-A
• rs868224632
• NM_022356.4:c.1840G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_022356.4(P3H1):​c.1840G>T​(p.Ala614Ser) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,810 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A614T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: P3H1 NM_022356.4 missense, splice_region
• Scores: Splicing: ADA: 0.9759
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57
• Publications: 5 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: Uncertain_significance. The variant received 1 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.1840G>T	p.Ala614Ser	missense splice_region	Exon 13 of 15	NP_071751.3
	P3H1	NM_001243246.2		c.1840G>T	p.Ala614Ser	missense splice_region	Exon 13 of 14	NP_001230175.1	Q32P28-3
	P3H1	NM_001146289.2		c.1840G>T	p.Ala614Ser	missense splice_region	Exon 13 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.1840G>T	p.Ala614Ser	missense splice_region	Exon 13 of 15	ENSP00000296388.5	Q32P28-1
	P3H1	ENST00000397054.7	TSL:1	c.1840G>T	p.Ala614Ser	missense splice_region	Exon 13 of 15	ENSP00000380245.3	Q32P28-4
	P3H1	ENST00000907902.1		c.2164G>T	p.Ala722Ser	missense splice_region	Exon 13 of 15	ENSP00000577961.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461810 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727220

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

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

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111952

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Osteogenesis imperfecta type 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.025	T
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.6	L
PhyloP100		7.6
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.29
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.58
MutPred		0.66		Gain of phosphorylation at S613 (P = 0.2808)
MVP		0.38
MPC		0.60
ClinPred		0.93	D
GERP RS		5.4
Varity_R		0.48
gMVP		0.76
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.77
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: rs868224632; hg19: chr1-43213468;