3-190120434-CG-CGG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_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

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.180
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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 id 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
P3H2NM_018192.4 linkc.297dupC p.Gly100ArgfsTer7 frameshift_variant Exon 1 of 15 ENST00000319332.10 NP_060662.2 Q8IVL5-1
P3H2NM_001134418.2 linkc.-64+1768dupC intron_variant Intron 1 of 14 NP_001127890.1 Q8IVL5-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
P3H2ENST00000319332.10 linkc.297dupC p.Gly100ArgfsTer7 frameshift_variant Exon 1 of 15 1 NM_018192.4 ENSP00000316881.5 Q8IVL5-1
P3H2ENST00000427335.6 linkc.-64+1768dupC intron_variant Intron 1 of 14 1 ENSP00000408947.2 Q8IVL5-2
P3H2ENST00000426003.1 linkc.-64+1102dupC intron_variant Intron 1 of 3 4 ENSP00000394326.1 C9JSL4

Frequencies

GnomAD3 genomes
AF:
0.0000133
AC:
2
AN:
150570
Hom.:
0
Cov.:
32
show subpopulations
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
GnomAD4 exome
AF:
0.00000238
AC:
3
AN:
1258484
Hom.:
0
Cov.:
32
AF XY:
0.00000324
AC XY:
2
AN XY:
617734
show subpopulations
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:
0.0000347
Gnomad4 NFE exome
AF:
0.00000196
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000133
AC:
2
AN:
150570
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
73518
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000296
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

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

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs875989838; hg19: chr3-189838223; API