chr1-42747397-G-T

Position:

• chr1-42747397-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_022356.4(P3H1):​c.1930C>A​(p.Gln644Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00254 in 1,611,248 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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. Q644P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0032 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (56 hom.)
• Consequence: P3H1 NM_022356.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 3.02

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008805096).
• BP6: Variant 1-42747397-G-T is Benign according to our data. Variant chr1-42747397-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 468979.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0032 (488/152292) while in subpopulation EAS AF= 0.00521 (27/5184). AF 95% confidence interval is 0.00368. There are 7 homozygotes in gnomad4. There are 322 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
P3H1	NM_022356.4	c.1930C>A	p.Gln644Lys	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.1930C>A	p.Gln644Lys	missense_variant	14/15	1	NM_022356.4	ENSP00000296388.5

Frequencies

GnomAD3 genomes AF: 0.00321 AC: 488 AN: 152174 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00520

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0327

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00140

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00483 AC: 1192 AN: 246944 Hom.: 21 AF XY: 0.00470 AC XY: 630 AN XY: 134144

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000206

Gnomad EAS exome AF: 0.00371

Gnomad SAS exome AF: 0.000728

Gnomad FIN exome AF: 0.0372

Gnomad NFE exome AF: 0.00217

Gnomad OTH exome AF: 0.00977

GnomAD4 exome AF: 0.00247 AC: 3606 AN: 1458956 Hom.: 56 Cov.: 32 AF XY: 0.00244 AC XY: 1774 AN XY: 725586

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000449

Gnomad4 ASJ exome AF: 0.0000771

Gnomad4 EAS exome AF: 0.0142

Gnomad4 SAS exome AF: 0.000675

Gnomad4 FIN exome AF: 0.0383

Gnomad4 NFE exome AF: 0.000702

Gnomad4 OTH exome AF: 0.00305

GnomAD4 genome AF: 0.00320 AC: 488 AN: 152292 Hom.: 7 Cov.: 33 AF XY: 0.00432 AC XY: 322 AN XY: 74464

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00521

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.0327

Gnomad4 NFE AF: 0.00140

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000974 Hom.: 0

Bravo AF: 0.000722

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000229 AC: 1

ESP6500EA AF: 0.000469 AC: 4

ExAC AF: 0.00470 AC: 569

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000534

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Osteogenesis imperfecta type 8 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Osteogenesis Imperfecta, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 22, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	21
DANN	Benign	0.89
DEOGEN2	Benign	0.053	.;.;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.073
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.84	T;T;T
MetaRNN	Benign	0.0088	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.51	N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.84	N;N;N
REVEL	Benign	0.065
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.14, 0.13	.;B;B
Vest4		0.17
MVP		0.40
MPC		0.25
ClinPred		0.064	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.55

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: rs3738497; hg19: chr1-43213068;