5-132213965-CT-AA

Variant names:

• chr5-132213965-CT-AA
• NM_001365677.2:c.419_420delAGinsTT
• P4HA2 p.Gln140Leu

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM5

The NM_001017974.2(P4HA2):​c.419_420delAGinsTT​(p.Gln140Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q140R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: P4HA2 NM_001017974.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.24
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr5-132213966-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 372166.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001017974.2. 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.419_420delAGinsTT	p.Gln140Leu	missense	N/A	NP_001352606.1	O15460-1
	P4HA2	NM_001017974.2	MANE Select	c.419_420delAGinsTT	p.Gln140Leu	missense	N/A	NP_001017974.1	O15460-2
	P4HA2	NM_001142599.2		c.419_420delAGinsTT	p.Gln140Leu	missense	N/A	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.419_420delAGinsTT	p.Gln140Leu	missense	N/A	ENSP00000368398.2	O15460-1
	P4HA2	ENST00000360568.8	TSL:1 MANE Select	c.419_420delAGinsTT	p.Gln140Leu	missense	N/A	ENSP00000353772.3	O15460-2
	P4HA2	ENST00000166534.8	TSL:1	c.419_420delAGinsTT	p.Gln140Leu	missense	N/A	ENSP00000166534.4	O15460-1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.2

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr5-131549658;