NM_018192.4:c.2034+189G>C

Variant names:

• chr3-189963769-C-G
• rs1719581
• NM_018192.4:c.2034+189G>C

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+189G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 663,260 control chromosomes in the GnomAD database, including 18,931 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (3748 hom., cov: 32)
  • Exomes 𝑓: 0.24 (15183 hom.)
• Consequence: P3H2 NM_018192.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.45
• Publications: 1 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=-0.91).
• BP6: Variant 3-189963769-C-G is Benign according to our data. Variant chr3-189963769-C-G is described in ClinVar as [Benign]. Clinvar id is 1241801.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+189G>C		intron_variant	Intron 14 of 14	ENST00000319332.10	NP_060662.2
P3H2	NM_001134418.2	c.1491+189G>C		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+189G>C		intron_variant	Intron 14 of 14	1	NM_018192.4	ENSP00000316881.5
P3H2	ENST00000427335.6	c.1491+189G>C		intron_variant	Intron 14 of 14	1		ENSP00000408947.2
P3H2	ENST00000463171.5	n.444G>C		non_coding_transcript_exon_variant	Exon 3 of 3	5
P3H2	ENST00000490940.1	n.164+189G>C		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.215 AC: 32708 AN: 151978 Hom.: 3742 Cov.: 32

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.174

Gnomad ASJ AF: 0.250

Gnomad EAS AF: 0.175

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: 0.240 AC: 122544 AN: 511164 Hom.: 15183 Cov.: 6 AF XY: 0.240 AC XY: 65332 AN XY: 271908

African (AFR) AF: 0.135 AC: 1966 AN: 14528

American (AMR) AF: 0.137 AC: 3761 AN: 27466

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 3761 AN: 15238

East Asian (EAS) AF: 0.171 AC: 5431 AN: 31718

South Asian (SAS) AF: 0.219 AC: 11563 AN: 52856

European-Finnish (FIN) AF: 0.217 AC: 6588 AN: 30308

Middle Eastern (MID) AF: 0.221 AC: 460 AN: 2080

European-Non Finnish (NFE) AF: 0.267 AC: 82504 AN: 308856

Other (OTH) AF: 0.232 AC: 6510 AN: 28114

GnomAD4 genome AF: 0.215 AC: 32733 AN: 152096 Hom.: 3748 Cov.: 32 AF XY: 0.211 AC XY: 15681 AN XY: 74344

African (AFR) AF: 0.142 AC: 5892 AN: 41526

American (AMR) AF: 0.174 AC: 2658 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.250 AC: 869 AN: 3470

East Asian (EAS) AF: 0.175 AC: 904 AN: 5170

South Asian (SAS) AF: 0.215 AC: 1035 AN: 4822

European-Finnish (FIN) AF: 0.223 AC: 2352 AN: 10542

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

European-Non Finnish (NFE) AF: 0.269 AC: 18313 AN: 67962

Other (OTH) AF: 0.210 AC: 444 AN: 2114

Alfa AF: 0.138 Hom.: 252

Bravo AF: 0.206

Asia WGS AF: 0.186 AC: 652 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	-0.91
CADD	Benign	0.55
DANN	Benign	0.49
PhyloP100		-1.4
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: rs1719581; hg19: chr3-189681558; COSMIC: COSV60018095; COSMIC: COSV60018095;