rs202209556

Positions:

• chr1-42747295-G-C
• chr1-42747295-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_022356.4(P3H1):​c.2032C>G​(p.Leu678Val) 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 1,461,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: P3H1 NM_022356.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.469

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35794735).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
P3H1	NM_022356.4	c.2032C>G	p.Leu678Val	missense_variant	14/15	ENST00000296388.10	NP_071751.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
P3H1	ENST00000296388.10	c.2032C>G	p.Leu678Val	missense_variant	14/15	1	NM_022356.4	ENSP00000296388	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250832 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135636

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461234 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726842

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.052	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	.;.;T
Eigen	Benign	0.10
Eigen_PC	Benign	-0.074
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.83	T;D;D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-0.58	T
MutationAssessor	Pathogenic	3.1	M;M;M
MutationTaster	Benign	0.73	D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.16
Sift	Uncertain	0.017	D;T;D
Sift4G	Benign	0.11	T;T;T
Polyphen		1.0, 1.0	.;D;D
Vest4		0.71
MutPred		0.26		Gain of MoRF binding (P = 0.082);Gain of MoRF binding (P = 0.082);Gain of MoRF binding (P = 0.082);
MVP		0.35
MPC		0.71
ClinPred		0.63	D
GERP RS		-0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.24
gMVP		0.55

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

Publications

LitVar

Other links and lift over

dbSNP: rs202209556; hg19: chr1-43212966;