rs4361509

Variant names:

• chr5-132201060-G-A
• rs4361509
• NM_001365677.2:c.1252-2128C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001365677.2(P4HA2):​c.1252-2128C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.343 in 152,202 control chromosomes in the GnomAD database, including 10,044 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.34 (10043 hom., cov: 33)
  • Exomes 𝑓: 1.0 (1 hom.)
• Consequence: P4HA2 NM_001365677.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.289
• Publications: 12 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: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ENSG00000224431 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.442 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P4HA2	NM_001365677.2	c.1252-2128C>T		intron_variant	Intron 10 of 14	ENST00000379104.7	NP_001352606.1
P4HA2	NM_001017974.2	c.1252-2128C>T		intron_variant	Intron 10 of 14	ENST00000360568.8	NP_001017974.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P4HA2	ENST00000379104.7	c.1252-2128C>T		intron_variant	Intron 10 of 14	1	NM_001365677.2	ENSP00000368398.2
P4HA2	ENST00000360568.8	c.1252-2128C>T		intron_variant	Intron 10 of 14	1	NM_001017974.2	ENSP00000353772.3

Frequencies

GnomAD3 genomes AF: 0.344 AC: 52269 AN: 152082 Hom.: 10043 Cov.: 33

Gnomad AFR AF: 0.195

Gnomad AMI AF: 0.595

Gnomad AMR AF: 0.329

Gnomad ASJ AF: 0.355

Gnomad EAS AF: 0.210

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.403

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.447

Gnomad OTH AF: 0.381

GnomAD4 exome AF: 1.00 AC: 2 AN: 2 Hom.: 1 Cov.: 0 AF XY: 1.00 AC XY: 2 AN XY: 2

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 1.00 AC: 2 AN: 2

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.343 AC: 52273 AN: 152200 Hom.: 10043 Cov.: 33 AF XY: 0.334 AC XY: 24886 AN XY: 74410

African (AFR) AF: 0.195 AC: 8113 AN: 41516

American (AMR) AF: 0.328 AC: 5023 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 1231 AN: 3472

East Asian (EAS) AF: 0.210 AC: 1088 AN: 5184

South Asian (SAS) AF: 0.157 AC: 760 AN: 4828

European-Finnish (FIN) AF: 0.403 AC: 4260 AN: 10582

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.447 AC: 30374 AN: 68008

Other (OTH) AF: 0.376 AC: 792 AN: 2108

Alfa AF: 0.350 Hom.: 1894

Bravo AF: 0.338

Asia WGS AF: 0.188 AC: 652 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.9
DANN	Benign	0.75
PhyloP100		0.29
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4361509; hg19: chr5-131536753; COSMIC: COSV51324177;