3-189958007-G-C

Variant summary

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

The NM_018192.4(P3H2):​c.2035-3C>G variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Consequence

P3H2
NM_018192.4 splice_region, intron

Scores

2
Splicing: ADA: 0.9998
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.53
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]

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ACMG classification

Classification made for transcript

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
P3H2NM_018192.4 linkc.2035-3C>G splice_region_variant, intron_variant ENST00000319332.10 NP_060662.2 Q8IVL5-1
P3H2NM_001134418.2 linkc.1492-3C>G splice_region_variant, intron_variant NP_001127890.1 Q8IVL5-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
P3H2ENST00000319332.10 linkc.2035-3C>G splice_region_variant, intron_variant 1 NM_018192.4 ENSP00000316881.5 Q8IVL5-1
P3H2ENST00000427335.6 linkc.1492-3C>G splice_region_variant, intron_variant 1 ENSP00000408947.2 Q8IVL5-2
P3H2ENST00000490940.1 linkn.165-3C>G splice_region_variant, intron_variant 2

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
28
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 07, 2022This sequence change falls in intron 14 of the P3H2 gene. It does not directly change the encoded amino acid sequence of the P3H2 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 1371159). This variant has not been reported in the literature in individuals affected with P3H2-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.40
CADD
Benign
19
DANN
Benign
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.91
SpliceAI score (max)
0.96
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.96
Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-189675796; API