chr3-189957778-C-G

Variant names:

• chr3-189957778-C-G
• rs145678898
• NM_018192.4:c.*134G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018192.4(P3H2):​c.*134G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 535,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000019 (0 hom.)
• Consequence: P3H2 NM_018192.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.666
• Publications: 0 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 Gene-Disease associations (from GenCC):

• myopia, high, with cataract and vitreoretinal degeneration

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P3H2	NM_018192.4	c.*134G>C		3_prime_UTR_variant	Exon 15 of 15	ENST00000319332.10	NP_060662.2
P3H2	NM_001134418.2	c.*134G>C		3_prime_UTR_variant	Exon 15 of 15		NP_001127890.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P3H2	ENST00000319332.10	c.*134G>C		3_prime_UTR_variant	Exon 15 of 15	1	NM_018192.4	ENSP00000316881.5
P3H2	ENST00000427335.6	c.*134G>C		3_prime_UTR_variant	Exon 15 of 15	1		ENSP00000408947.2
P3H2	ENST00000490940.1	n.391G>C		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000187 AC: 1 AN: 535258 Hom.: 0 Cov.: 6 AF XY: 0.00 AC XY: 0 AN XY: 287808

⚠️ 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: 14770

American (AMR) AF: 0.00 AC: 0 AN: 30252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17514

East Asian (EAS) AF: 0.00 AC: 0 AN: 31718

South Asian (SAS) AF: 0.00 AC: 0 AN: 54476

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2234

European-Non Finnish (NFE) AF: 0.00000312 AC: 1 AN: 320212

Other (OTH) AF: 0.00 AC: 0 AN: 29454

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	8.2
DANN	Benign	0.85
PhyloP100		0.67

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: rs145678898; hg19: chr3-189675567;