rs143985056

Variant names:

• chr3-189963671-C-T
• rs143985056
• NM_018192.4:c.2034+287G>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.2034+287G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00905 in 388,160 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (38 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (29 hom.)
• Consequence: P3H2 NM_018192.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.794
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.03).
• BP6: Variant 3-189963671-C-T is Benign according to our data. Variant chr3-189963671-C-T is described in ClinVar as [Benign]. Clinvar id is 1235572.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0149 (2267/152130) while in subpopulation AFR AF = 0.0482 (1998/41492). AF 95% confidence interval is 0.0464. There are 38 homozygotes in GnomAd4. There are 1086 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 38 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P3H2	NM_018192.4	c.2034+287G>A		intron_variant	Intron 14 of 14	ENST00000319332.10	NP_060662.2
P3H2	NM_001134418.2	c.1491+287G>A		intron_variant	Intron 14 of 14		NP_001127890.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P3H2	ENST00000319332.10	c.2034+287G>A		intron_variant	Intron 14 of 14	1	NM_018192.4	ENSP00000316881.5
P3H2	ENST00000427335.6	c.1491+287G>A		intron_variant	Intron 14 of 14	1		ENSP00000408947.2
P3H2	ENST00000463171.5	n.542G>A		non_coding_transcript_exon_variant	Exon 3 of 3	5
P3H2	ENST00000490940.1	n.164+287G>A		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.0149 AC: 2266 AN: 152012 Hom.: 38 Cov.: 32

Gnomad AFR AF: 0.0483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00806

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0216

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0105

GnomAD4 exome AF: 0.00528 AC: 1246 AN: 236030 Hom.: 29 Cov.: 0 AF XY: 0.00626 AC XY: 781 AN XY: 124800

African (AFR) AF: 0.0439 AC: 335 AN: 7630

American (AMR) AF: 0.00355 AC: 43 AN: 12122

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6970

East Asian (EAS) AF: 0.0000732 AC: 1 AN: 13656

South Asian (SAS) AF: 0.0236 AC: 760 AN: 32146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11022

Middle Eastern (MID) AF: 0.00514 AC: 5 AN: 972

European-Non Finnish (NFE) AF: 0.000253 AC: 35 AN: 138272

Other (OTH) AF: 0.00506 AC: 67 AN: 13240

GnomAD4 genome AF: 0.0149 AC: 2267 AN: 152130 Hom.: 38 Cov.: 32 AF XY: 0.0146 AC XY: 1086 AN XY: 74374

African (AFR) AF: 0.0482 AC: 1998 AN: 41492

American (AMR) AF: 0.00805 AC: 123 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.0216 AC: 104 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 67984

Other (OTH) AF: 0.0104 AC: 22 AN: 2110

Alfa AF: 0.0122 Hom.: 3

Bravo AF: 0.0172

Asia WGS AF: 0.0180 AC: 62 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 14, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.65
DANN	Benign	0.68
PhyloP100		-0.79
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: rs143985056; hg19: chr3-189681460;