1-42750190-G-C

Position:

• chr1-42750190-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_022356.4(P3H1):​c.1716C>G​(p.Ile572Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000822 in 1,459,736 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Synonymous variant affecting the same amino acid position (i.e. I572I) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: P3H1 NM_022356.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.134

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
P3H1	NM_022356.4	c.1716C>G	p.Ile572Met	missense_variant	11/15	ENST00000296388.10	NP_071751.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
P3H1	ENST00000296388.10	c.1716C>G	p.Ile572Met	missense_variant	11/15	1	NM_022356.4	ENSP00000296388.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000405 AC: 1 AN: 247038 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133636

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: 0.00000896

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1459736 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 725874

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: 0.00000990

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	12
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	.;.;T
Eigen	Benign	-0.014
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.75	T;T;T
M_CAP	Benign	0.068	D
MetaRNN	Uncertain	0.63	D;D;D
MetaSVM	Benign	-0.75	T
MutationAssessor	Uncertain	2.6	M;M;M
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.18
Sift	Uncertain	0.0080	D;D;D
Sift4G	Uncertain	0.016	D;D;D
Polyphen		0.98, 0.90	.;D;P
Vest4		0.54
MutPred		0.36		Gain of disorder (P = 0.0697);Gain of disorder (P = 0.0697);Gain of disorder (P = 0.0697);
MVP		0.39
MPC		0.67
ClinPred		0.71	D
GERP RS		-1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35500164; hg19: chr1-43215861;