rs117688924

chr3-189995368-C-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_018192.4(P3H2):c.555G>T(p.Gln185His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000846 in 1,614,062 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00080 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00085 (5 hom.)
• Consequence: P3H2 NM_018192.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.0850

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00795579).
• BP6: Variant 3-189995368-C-A is Benign according to our data. Variant chr3-189995368-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 547920.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000802 (122/152214) while in subpopulation SAS AF= 0.00932 (45/4828). AF 95% confidence interval is 0.00716. There are 0 homozygotes in gnomad4. There are 66 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
P3H2	NM_018192.4	c.555G>T	p.Gln185His	missense_variant	2/15	ENST00000319332.10
P3H2	NM_001134418.2	c.12G>T	p.Gln4His	missense_variant	2/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
P3H2	ENST00000319332.10	c.555G>T	p.Gln185His	missense_variant	2/15	1	NM_018192.4	P1
P3H2	ENST00000427335.6	c.12G>T	p.Gln4His	missense_variant	2/15	1
P3H2	ENST00000444866.5	c.12G>T	p.Gln4His	missense_variant	2/4	4
P3H2	ENST00000426003.1	c.12G>T	p.Gln4His	missense_variant	2/4	4

Frequencies

GnomAD3 genomes AF: 0.000802 AC: 122 AN: 152096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00931

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00121 AC: 303 AN: 251338 Hom.: 0 AF XY: 0.00149 AC XY: 203 AN XY: 135828

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00614

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000660

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000851 AC: 1244 AN: 1461848 Hom.: 5 Cov.: 31 AF XY: 0.000991 AC XY: 721 AN XY: 727226

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.000648

Gnomad4 ASJ exome AF: 0.00287

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00623

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000421

Gnomad4 OTH exome AF: 0.00147

GnomAD4 genome AF: 0.000802 AC: 122 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.000887 AC XY: 66 AN XY: 74434

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000916

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00932

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000676

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.000866 Hom.: 1

Bravo AF: 0.000593

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00123 AC: 150

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Myopia, high, with cataract and vitreoretinal degeneration Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 10, 2017	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.;.;.
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.93	D;T;T;T
MetaRNN	Benign	0.0080	T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.8	L;.;.;.
MutationTaster	Benign	0.92	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.6	N;N;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.011	D;D;D;D
Sift4G	Uncertain	0.029	D;D;.;.
Polyphen		0.99	D;.;.;.
Vest4		0.41
MutPred		0.36		Gain of disorder (P = 0.1474);.;.;.;
MVP		0.32
MPC		0.28
ClinPred		0.055	T
GERP RS		2.4
Varity_R		0.083
gMVP		0.53

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

Publications

LitVar

Other links and lift over

dbSNP: rs117688924; hg19: chr3-189713157; COSMIC: COSV100078772;