1-42757902-C-T

Variant names:

• chr1-42757902-C-T
• rs866278783
• NM_022356.4:c.961G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022356.4(P3H1):​c.961G>A​(p.Val321Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V321V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: P3H1 NM_022356.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.67

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.051348776).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P3H1	NM_022356.4	c.961G>A	p.Val321Ile	missense_variant	Exon 5 of 15	ENST00000296388.10	NP_071751.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P3H1	ENST00000296388.10	c.961G>A	p.Val321Ile	missense_variant	Exon 5 of 15	1	NM_022356.4	ENSP00000296388.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Osteogenesis imperfecta type 8 Uncertain:1

Jun 07, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals with a P3H1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on P3H1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with isoleucine at codon 321 of the P3H1 protein (p.Val321Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	6.6
DANN	Benign	0.75
DEOGEN2	Benign	0.069	.;.;T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.70	T;T;T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.051	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.65	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.32	N;N;N
REVEL	Benign	0.024
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0020, 0.0	.;B;B
Vest4		0.080
MutPred		0.36		Gain of ubiquitination at K325 (P = 0.1047);Gain of ubiquitination at K325 (P = 0.1047);Gain of ubiquitination at K325 (P = 0.1047);
MVP		0.19
MPC		0.15
ClinPred		0.43	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.019
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs866278783; hg19: chr1-43223573;