11-74269669-T-A

Variant names:

• chr11-74269669-T-A
• rs1341353421
• NM_182904.5:c.1450A>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_182904.5(P4HA3):​c.1450A>T​(p.Ser484Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,613,724 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: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: P4HA3 NM_182904.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.81
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.754

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182904.5. 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
	P4HA3	NM_182904.5	MANE Select	c.1450A>T	p.Ser484Cys	missense	Exon 11 of 13	NP_878907.1	Q7Z4N8-1
	P4HA3	NM_001288748.2		c.1450A>T	p.Ser484Cys	missense	Exon 11 of 13	NP_001275677.1	Q7Z4N8-3
	P4HA3	NR_110031.2		n.1285A>T		non_coding_transcript_exon	Exon 10 of 12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P4HA3	ENST00000331597.9	TSL:1 MANE Select	c.1450A>T	p.Ser484Cys	missense	Exon 11 of 13	ENSP00000332170.4	Q7Z4N8-1
	P4HA3	ENST00000524388.5	TSL:1	n.*852A>T		non_coding_transcript_exon	Exon 12 of 16	ENSP00000433860.1	Q7Z4N8-2
	P4HA3	ENST00000525968.1	TSL:1	n.*941A>T		non_coding_transcript_exon	Exon 10 of 12	ENSP00000431227.1	E9PM97

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250476 AF XY: 0.00000739

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461566 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727068

African (AFR) AF: 0.0000896 AC: 3 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111818

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74330

African (AFR) AF: 0.0000724 AC: 3 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

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	Uncertain	0.47
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.42	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.048	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.8
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.50		Loss of MoRF binding (P = 0.1145)
MVP		0.88
MPC		0.39
ClinPred		0.95	D
GERP RS		5.3
Varity_R		0.45
gMVP		0.63
Mutation Taster		=53/47	polymorphism

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: rs1341353421; hg19: chr11-73980714;