NM_018192.4:c.*202_*211dupCTCTCTCTCT

Variant names:

• chr3-189957700-A-AAGAGAGAGAG
• rs3062112
• NM_018192.4:c.*202_*211dupCTCTCTCTCT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_018192.4(P3H2):​c.*202_*211dupCTCTCTCTCT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.016 (24 hom., cov: 0)
  • Exomes 𝑓: 0.010 (5 hom.)
• Consequence: P3H2 NM_018192.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.38
• 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 -10 ACMG points.

• BP6: Variant 3-189957700-A-AAGAGAGAGAG is Benign according to our data. Variant chr3-189957700-A-AAGAGAGAGAG is described in ClinVar as [Likely_benign]. Clinvar id is 1195289.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0164 (2413/147564) while in subpopulation AFR AF = 0.0257 (1031/40124). AF 95% confidence interval is 0.0244. There are 24 homozygotes in GnomAd4. There are 1159 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P3H2	NM_018192.4	c.*202_*211dupCTCTCTCTCT		3_prime_UTR_variant	Exon 15 of 15	ENST00000319332.10	NP_060662.2
P3H2	NM_001134418.2	c.*202_*211dupCTCTCTCTCT		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.*202_*211dupCTCTCTCTCT		3_prime_UTR_variant	Exon 15 of 15	1	NM_018192.4	ENSP00000316881.5
P3H2	ENST00000427335.6	c.*202_*211dupCTCTCTCTCT		3_prime_UTR_variant	Exon 15 of 15	1		ENSP00000408947.2
P3H2	ENST00000490940.1	n.459_468dupCTCTCTCTCT		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes AF: 0.0163 AC: 2410 AN: 147454 Hom.: 24 Cov.: 0

Gnomad AFR AF: 0.0257

Gnomad AMI AF: 0.00116

Gnomad AMR AF: 0.0189

Gnomad ASJ AF: 0.0319

Gnomad EAS AF: 0.00181

Gnomad SAS AF: 0.00683

Gnomad FIN AF: 0.00256

Gnomad MID AF: 0.0162

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.0198

GnomAD4 exome AF: 0.0103 AC: 4065 AN: 395278 Hom.: 5 Cov.: 0 AF XY: 0.00987 AC XY: 2095 AN XY: 212352

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0203 AC: 228 AN: 11218

American (AMR) AF: 0.0152 AC: 258 AN: 16966

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 287 AN: 11718

East Asian (EAS) AF: 0.00112 AC: 29 AN: 26002

South Asian (SAS) AF: 0.00487 AC: 211 AN: 43364

European-Finnish (FIN) AF: 0.00333 AC: 78 AN: 23396

Middle Eastern (MID) AF: 0.00946 AC: 16 AN: 1692

European-Non Finnish (NFE) AF: 0.0112 AC: 2669 AN: 238540

Other (OTH) AF: 0.0129 AC: 289 AN: 22382

⚠️ 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 AF: 0.0164 AC: 2413 AN: 147564 Hom.: 24 Cov.: 0 AF XY: 0.0162 AC XY: 1159 AN XY: 71684

African (AFR) AF: 0.0257 AC: 1031 AN: 40124

American (AMR) AF: 0.0188 AC: 278 AN: 14760

Ashkenazi Jewish (ASJ) AF: 0.0319 AC: 109 AN: 3416

East Asian (EAS) AF: 0.00182 AC: 9 AN: 4956

South Asian (SAS) AF: 0.00706 AC: 32 AN: 4534

European-Finnish (FIN) AF: 0.00256 AC: 25 AN: 9776

Middle Eastern (MID) AF: 0.0175 AC: 5 AN: 286

European-Non Finnish (NFE) AF: 0.0132 AC: 884 AN: 66812

Other (OTH) AF: 0.0191 AC: 39 AN: 2040

Alfa AF: 0.00501 Hom.: 390

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 06, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3062112; hg19: chr3-189675489;