NM_018192.4:c.297dupC

Variant names:

• chr3-190120434-C-CG
• rs875989838
• NM_018192.4:c.297dupC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_018192.4(P3H2):​c.297dupC​(p.Gly100ArgfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000355 in 1,409,054 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: P3H2 NM_018192.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.180
• Publications: 3 publications found

Genes affected

P3H2 (HGNC:19317): (prolyl 3-hydroxylase 2) This gene encodes a member of the prolyl 3-hydroxylase subfamily of 2-oxo-glutarate-dependent dioxygenases. These enzymes play a critical role in collagen chain assembly, stability and cross-linking by catalyzing post-translational 3-hydroxylation of proline residues. Mutations in this gene are associated with nonsyndromic severe myopia with cataract and vitreoretinal degeneration, and downregulation of this gene may play a role in breast cancer. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

P3H2-AS1 (HGNC:40886): (P3H2 antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-190120434-C-CG is Pathogenic according to our data. Variant chr3-190120434-C-CG is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2690665.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P3H2	NM_018192.4	c.297dupC	p.Gly100ArgfsTer7	frameshift_variant	Exon 1 of 15	ENST00000319332.10	NP_060662.2
P3H2	NM_001134418.2	c.-64+1768dupC		intron_variant	Intron 1 of 14		NP_001127890.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P3H2	ENST00000319332.10	c.297dupC	p.Gly100ArgfsTer7	frameshift_variant	Exon 1 of 15	1	NM_018192.4	ENSP00000316881.5

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 150570 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000296

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000642 AC: 3 AN: 46708 AF XY: 0.000111

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000302

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000526

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000238 AC: 3 AN: 1258484 Hom.: 0 Cov.: 32 AF XY: 0.00000324 AC XY: 2 AN XY: 617734

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25054

American (AMR) AF: 0.00 AC: 0 AN: 19556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19166

East Asian (EAS) AF: 0.00 AC: 0 AN: 27090

South Asian (SAS) AF: 0.00 AC: 0 AN: 63536

European-Finnish (FIN) AF: 0.0000347 AC: 1 AN: 28818

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3604

European-Non Finnish (NFE) AF: 0.00000196 AC: 2 AN: 1020344

Other (OTH) AF: 0.00 AC: 0 AN: 51316

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 150570 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73518

African (AFR) AF: 0.00 AC: 0 AN: 41152

American (AMR) AF: 0.00 AC: 0 AN: 15148

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 4974

South Asian (SAS) AF: 0.00 AC: 0 AN: 4664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10246

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000296 AC: 2 AN: 67626

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Myopia, high, with cataract and vitreoretinal degeneration Pathogenic:1

Jun 19, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.18
Mutation Taster		=7/193	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs875989838; hg19: chr3-189838223;