5-132198937-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001365677.2(P4HA2):c.1252-5C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000787 in 1,603,746 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0041 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (1 hom.)
• Consequence: P4HA2 NM_001365677.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.000009220
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.512

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 5-132198937-G-A is Benign according to our data. Variant chr5-132198937-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3041035.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 624 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
P4HA2	NM_001017974.2	c.1252-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000360568.8
P4HA2	NM_001365677.2	c.1252-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000379104.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
P4HA2	ENST00000360568.8	c.1252-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001017974.2	A1
P4HA2	ENST00000379104.7	c.1252-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001365677.2	P4

Frequencies

GnomAD3 genomes AF: 0.00410 AC: 624 AN: 152134 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00110 AC: 277 AN: 251390 Hom.: 3 AF XY: 0.000736 AC XY: 100 AN XY: 135870

Gnomad AFR exome AF: 0.0148

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000438 AC: 636 AN: 1451494 Hom.: 1 Cov.: 29 AF XY: 0.000356 AC XY: 257 AN XY: 722880

Gnomad4 AFR exome AF: 0.0153

Gnomad4 AMR exome AF: 0.000917

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000263

Gnomad4 OTH exome AF: 0.000816

GnomAD4 genome AF: 0.00411 AC: 626 AN: 152252 Hom.: 5 Cov.: 32 AF XY: 0.00394 AC XY: 293 AN XY: 74424

Gnomad4 AFR AF: 0.0142

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00213 Hom.: 2

Bravo AF: 0.00485

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

P4HA2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 12, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	1.7
Dann	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0000092
dbscSNV1_RF	Benign	0.0
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: rs73788824; hg19: chr5-131534630;