Genetic Variant P3H2:c.*208_*211dupCTCT (chr3-189957700-A-AAGAG) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBA1

The NM_018192.4(P3H2):c.*208_*211dupCTCT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.020 ( 55 hom., cov: 0)

Exomes 𝑓: 0.0073 ( 6 hom. )

Consequence

P3H2
NM_018192.4 3_prime_UTR

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.38

Publications

0 publications found

Variant links:

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

P3H2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP6

Variant 3-189957700-A-AAGAG is Benign according to our data. Variant chr3-189957700-A-AAGAG is described in ClinVar as [Benign]. Clinvar id is 1277801.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0586 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P3H2	NM_018192.4 link	c.208_211dupCTCT		3_prime_UTR_variant	Exon 15 of 15	ENST00000319332.10	NP_060662.2	Q8IVL5-1
P3H2	NM_001134418.2 link	c.208_211dupCTCT		3_prime_UTR_variant	Exon 15 of 15		NP_001127890.1	Q8IVL5-2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
P3H2	ENST00000319332.10 link	c.208_211dupCTCT	3_prime_UTR_variant	Exon 15 of 15	1	NM_018192.4	ENSP00000316881.5	Q8IVL5-1
P3H2	ENST00000427335.6 link	c.208_211dupCTCT	3_prime_UTR_variant	Exon 15 of 15	1		ENSP00000408947.2	Q8IVL5-2
P3H2	ENST00000490940.1 link	n.465_468dupCTCT	non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.0196

AC:

2896

AN:

147444

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0606

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0113

Gnomad ASJ

AF:

0.000879

Gnomad EAS

AF:

0.00624

Gnomad SAS

AF:

0.00220

Gnomad FIN

AF:

0.00308

Gnomad MID

AF:

0.00649

Gnomad NFE

AF:

0.00301

Gnomad OTH

AF:

0.0134

GnomAD4 exome

AF:

0.00727

AC:

2856

AN:

392910

Hom.:

Cov.:

AF XY:

0.00682

AC XY:

1439

AN XY:

211052

show subpopulations

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

African (AFR)

AF:

0.0557

AC:

624

AN:

11198

American (AMR)

AF:

0.00793

AC:

134

AN:

16908

Ashkenazi Jewish (ASJ)

AF:

0.00248

AC:

AN:

11690

East Asian (EAS)

AF:

0.00582

AC:

151

AN:

25958

South Asian (SAS)

AF:

0.00336

AC:

145

AN:

43118

European-Finnish (FIN)

AF:

0.00745

AC:

172

AN:

23098

Middle Eastern (MID)

AF:

0.00657

AC:

AN:

1674

European-Non Finnish (NFE)

AF:

0.00572

AC:

1355

AN:

237004

Other (OTH)

AF:

0.0106

AC:

235

AN:

22262

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.348

Heterozygous variant carriers

141

282

422

563

704

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0197

AC:

2902

AN:

147554

Hom.:

Cov.:

AF XY:

0.0192

AC XY:

1379

AN XY:

71672

show subpopulations

African (AFR)

AF:

0.0606

AC:

2431

AN:

40134

American (AMR)

AF:

0.0112

AC:

166

AN:

14758

Ashkenazi Jewish (ASJ)

AF:

0.000879

AC:

AN:

3414

East Asian (EAS)

AF:

0.00625

AC:

AN:

4958

South Asian (SAS)

AF:

0.00243

AC:

AN:

4536

European-Finnish (FIN)

AF:

0.00308

AC:

AN:

9754

Middle Eastern (MID)

AF:

0.00699

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.00301

AC:

201

AN:

66814

Other (OTH)

AF:

0.0132

AC:

AN:

2040

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

133

266

399

532

665

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000477

Hom.:

390

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Nov 06, 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

PhyloP100

1.4

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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3-189957700-A-AAGAG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over