5-132198235-C-T

Variant names:

• chr5-132198235-C-T
• NM_001365677.2:c.1342G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001365677.2(P4HA2):​c.1342G>A​(p.Gly448Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: P4HA2 NM_001365677.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57
• Publications: 0 publications found

Genes affected

P4HA2 (HGNC:8547): (prolyl 4-hydroxylase subunit alpha 2) This gene encodes a component of prolyl 4-hydroxylase, a key enzyme in collagen synthesis composed of two identical alpha subunits and two beta subunits. The encoded protein is one of several different types of alpha subunits and provides the major part of the catalytic site of the active enzyme. In collagen and related proteins, prolyl 4-hydroxylase catalyzes the formation of 4-hydroxyproline that is essential to the proper three-dimensional folding of newly synthesized procollagen chains. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

P4HA2 Gene-Disease associations (from GenCC):

• myopia

  Inheritance: AD Classification: STRONG Submitted by: G2P
• myopia 25, autosomal dominant

  Inheritance: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.952

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365677.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P4HA2	NM_001365677.2	MANE Plus Clinical	c.1342G>A	p.Gly448Arg	missense	Exon 12 of 15	NP_001352606.1	O15460-1
	P4HA2	NM_001017974.2	MANE Select	c.1365+86G>A		intron	N/A	NP_001017974.1	O15460-2
	P4HA2	NM_001142599.2		c.1342G>A	p.Gly448Arg	missense	Exon 13 of 16	NP_001136071.1	O15460-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P4HA2	ENST00000379104.7	TSL:1 MANE Plus Clinical	c.1342G>A	p.Gly448Arg	missense	Exon 12 of 15	ENSP00000368398.2	O15460-1
	P4HA2	ENST00000166534.8	TSL:1	c.1342G>A	p.Gly448Arg	missense	Exon 13 of 16	ENSP00000166534.4	O15460-1
	P4HA2	ENST00000360568.8	TSL:1 MANE Select	c.1365+86G>A		intron	N/A	ENSP00000353772.3	O15460-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		7.6
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.9	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.82		Gain of methylation at G448 (P = 0.0263)
MVP		0.93
MPC		0.94
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.58
gMVP		0.84
Mutation Taster		=14/86	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.42		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.42		Position offset: 36

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

Other links and lift over

hg19: chr5-131533928;