rs779625120

Variant names:

• chr11-74273567-C-A
• rs779625120
• NM_182904.5:c.1376G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-74273567-C-A
• chr11-74273567-C-T

Variant summary

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

The NM_182904.5(P4HA3):​c.1376G>T​(p.Arg459Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000712 in 1,405,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. R459Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: P4HA3 NM_182904.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.77
• Publications: 0 publications found

Genes affected

P4HA3 (HGNC:30135): (prolyl 4-hydroxylase subunit alpha 3) 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. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

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, 0.969

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P4HA3	NM_182904.5	c.1376G>T	p.Arg459Leu	missense_variant	Exon 10 of 13	ENST00000331597.9	NP_878907.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P4HA3	ENST00000331597.9	c.1376G>T	p.Arg459Leu	missense_variant	Exon 10 of 13	1	NM_182904.5	ENSP00000332170.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.12e-7 AC: 1 AN: 1405178 Hom.: 0 Cov.: 30 AF XY: 0.00000143 AC XY: 1 AN XY: 698218

African (AFR) AF: 0.00 AC: 0 AN: 30178

American (AMR) AF: 0.00 AC: 0 AN: 36072

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24932

East Asian (EAS) AF: 0.00 AC: 0 AN: 36304

South Asian (SAS) AF: 0.0000132 AC: 1 AN: 75882

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5584

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1086122

Other (OTH) AF: 0.00 AC: 0 AN: 57876

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	4.4	H;H
PhyloP100		4.8
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.88		Loss of MoRF binding (P = 0.0088);Loss of MoRF binding (P = 0.0088);
MVP		0.89
MPC		0.44
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.94
gMVP		0.95
Mutation Taster		=41/59	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs779625120; hg19: chr11-73984612;