3-189957972-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018192.4(P3H2):c.2067T>G(p.Ile689Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: P3H2 NM_018192.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.184

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05828911).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
P3H2	NM_018192.4	c.2067T>G	p.Ile689Met	missense_variant	15/15	ENST00000319332.10
P3H2	NM_001134418.2	c.1524T>G	p.Ile508Met	missense_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
P3H2	ENST00000319332.10	c.2067T>G	p.Ile689Met	missense_variant	15/15	1	NM_018192.4	P1
P3H2	ENST00000427335.6	c.1524T>G	p.Ile508Met	missense_variant	15/15	1
P3H2	ENST00000490940.1	n.197T>G		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 15, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with P3H2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 689 of the P3H2 protein (p.Ile689Met). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	7.4
Dann	Benign	0.12
DEOGEN2	Benign	0.049	T;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.058	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.55	N;.
MutationTaster	Benign	0.97	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	1.0	N;N
REVEL	Benign	0.035
Sift	Benign	1.0	T;T
Sift4G	Benign	0.41	T;T
Polyphen		0.0020	B;.
Vest4		0.066
MutPred		0.25		Gain of disorder (P = 0.0642);.;
MVP		0.19
MPC		0.059
ClinPred		0.35	T
GERP RS		0.82
Varity_R		0.024
gMVP		0.37

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-189675761;