chr3-189957778-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018192.4(P3H2):​c.*134G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0146 in 687,132 control chromosomes in the GnomAD database, including 115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (15 hom., cov: 31)
  • Exomes 𝑓: 0.016 (100 hom.)
• Consequence: P3H2 NM_018192.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.666
• 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 Gene-Disease associations (from GenCC):

• myopia, high, with cataract and vitreoretinal degeneration

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 3-189957778-C-T is Benign according to our data. Variant chr3-189957778-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1198632.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0112 (1701/151920) while in subpopulation SAS AF = 0.0244 (117/4804). AF 95% confidence interval is 0.0208. There are 15 homozygotes in GnomAd4. There are 802 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018192.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P3H2	NM_018192.4	MANE Select	c.*134G>A		3_prime_UTR	Exon 15 of 15	NP_060662.2
	P3H2	NM_001134418.2		c.*134G>A		3_prime_UTR	Exon 15 of 15	NP_001127890.1	Q8IVL5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P3H2	ENST00000319332.10	TSL:1 MANE Select	c.*134G>A		3_prime_UTR	Exon 15 of 15	ENSP00000316881.5	Q8IVL5-1
	P3H2	ENST00000427335.6	TSL:1	c.*134G>A		3_prime_UTR	Exon 15 of 15	ENSP00000408947.2	Q8IVL5-2
	P3H2	ENST00000895815.1		c.*134G>A		3_prime_UTR	Exon 15 of 15	ENSP00000565874.1

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1702 AN: 151800 Hom.: 15 Cov.: 31

Gnomad AFR AF: 0.00288

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.0112

Gnomad ASJ AF: 0.0265

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.0241

Gnomad FIN AF: 0.00561

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0160

Gnomad OTH AF: 0.0158

GnomAD4 exome AF: 0.0156 AC: 8334 AN: 535212 Hom.: 100 Cov.: 6 AF XY: 0.0165 AC XY: 4739 AN XY: 287776

African (AFR) AF: 0.00366 AC: 54 AN: 14770

American (AMR) AF: 0.00955 AC: 289 AN: 30252

Ashkenazi Jewish (ASJ) AF: 0.0246 AC: 430 AN: 17508

East Asian (EAS) AF: 0.0000631 AC: 2 AN: 31718

South Asian (SAS) AF: 0.0252 AC: 1372 AN: 54474

European-Finnish (FIN) AF: 0.00621 AC: 215 AN: 34626

Middle Eastern (MID) AF: 0.0461 AC: 103 AN: 2232

European-Non Finnish (NFE) AF: 0.0168 AC: 5388 AN: 320184

Other (OTH) AF: 0.0163 AC: 481 AN: 29448

GnomAD4 genome AF: 0.0112 AC: 1701 AN: 151920 Hom.: 15 Cov.: 31 AF XY: 0.0108 AC XY: 802 AN XY: 74242

African (AFR) AF: 0.00285 AC: 118 AN: 41438

American (AMR) AF: 0.0112 AC: 171 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0265 AC: 92 AN: 3470

East Asian (EAS) AF: 0.000388 AC: 2 AN: 5156

South Asian (SAS) AF: 0.0244 AC: 117 AN: 4804

European-Finnish (FIN) AF: 0.00561 AC: 59 AN: 10522

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0160 AC: 1088 AN: 67944

Other (OTH) AF: 0.0157 AC: 33 AN: 2106

Alfa AF: 0.0132 Hom.: 11

Bravo AF: 0.0111

Asia WGS AF: 0.0120 AC: 42 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	8.7
DANN	Benign	0.81
PhyloP100		0.67
Mutation Taster		=100/0	polymorphism

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;