3-189963695-C-T

Variant names:

• chr3-189963695-C-T
• rs837679
• NM_018192.4:c.2034+263G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018192.4(P3H2):​c.2034+263G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.23 in 442,598 control chromosomes in the GnomAD database, including 12,478 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3690 hom., cov: 32)
  • Exomes 𝑓: 0.24 (8788 hom.)
• Consequence: P3H2 NM_018192.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.72
• 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=-1.0).
• BP6: Variant 3-189963695-C-T is Benign according to our data. Variant chr3-189963695-C-T is described in ClinVar as [Benign]. Clinvar id is 1243765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P3H2	NM_018192.4	c.2034+263G>A		intron_variant	Intron 14 of 14	ENST00000319332.10	NP_060662.2
P3H2	NM_001134418.2	c.1491+263G>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+263G>A		intron_variant	Intron 14 of 14	1	NM_018192.4	ENSP00000316881.5
P3H2	ENST00000427335.6	c.1491+263G>A		intron_variant	Intron 14 of 14	1		ENSP00000408947.2
P3H2	ENST00000463171.5	n.518G>A		non_coding_transcript_exon_variant	Exon 3 of 3	5
P3H2	ENST00000490940.1	n.164+263G>A		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32337 AN: 152060 Hom.: 3686 Cov.: 32

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.235

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.250

Gnomad EAS AF: 0.173

Gnomad SAS AF: 0.214

Gnomad FIN AF: 0.223

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.210

GnomAD4 exome AF: 0.239 AC: 69526 AN: 290420 Hom.: 8788 Cov.: 3 AF XY: 0.239 AC XY: 36799 AN XY: 153650

African (AFR) AF: 0.125 AC: 1109 AN: 8842

American (AMR) AF: 0.146 AC: 2051 AN: 14086

Ashkenazi Jewish (ASJ) AF: 0.252 AC: 2218 AN: 8802

East Asian (EAS) AF: 0.170 AC: 2946 AN: 17376

South Asian (SAS) AF: 0.216 AC: 8191 AN: 37928

European-Finnish (FIN) AF: 0.218 AC: 3157 AN: 14450

Middle Eastern (MID) AF: 0.226 AC: 273 AN: 1208

European-Non Finnish (NFE) AF: 0.267 AC: 45734 AN: 171196

Other (OTH) AF: 0.233 AC: 3847 AN: 16532

GnomAD4 genome AF: 0.213 AC: 32353 AN: 152178 Hom.: 3690 Cov.: 32 AF XY: 0.208 AC XY: 15495 AN XY: 74384

African (AFR) AF: 0.133 AC: 5522 AN: 41544

American (AMR) AF: 0.173 AC: 2645 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 869 AN: 3472

East Asian (EAS) AF: 0.173 AC: 896 AN: 5174

South Asian (SAS) AF: 0.215 AC: 1035 AN: 4824

European-Finnish (FIN) AF: 0.223 AC: 2361 AN: 10584

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.269 AC: 18317 AN: 67982

Other (OTH) AF: 0.209 AC: 442 AN: 2110

Alfa AF: 0.229 Hom.: 535

Bravo AF: 0.203

Asia WGS AF: 0.186 AC: 651 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

- -

Jun 28, 2018

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	0.54
DANN	Benign	0.52
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs837679; hg19: chr3-189681484;