11-74285811-A-G

Position:

• chr11-74285811-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_182904.5(P4HA3):​c.1108T>C​(p.Trp370Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: P4HA3 NM_182904.5 missense, splice_region
• Scores: Splicing: ADA: 0.0005360
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.71

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]

P4HA3 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20911619).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
P4HA3	NM_182904.5	c.1108T>C	p.Trp370Arg	missense_variant, splice_region_variant	7/13	ENST00000331597.9	NP_878907.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
P4HA3	ENST00000331597.9	c.1108T>C	p.Trp370Arg	missense_variant, splice_region_variant	7/13	1	NM_182904.5	ENSP00000332170.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 25, 2023

The c.1108T>C (p.W370R) alteration is located in exon 7 (coding exon 7) of the P4HA3 gene. This alteration results from a T to C substitution at nucleotide position 1108, causing the tryptophan (W) at amino acid position 370 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	20
DANN	Benign	0.76
DEOGEN2	Benign	0.16	T;.
Eigen	Benign	-0.27
Eigen_PC	Benign	0.028
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.70	T;T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.26	N;N
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	0.60	N;N
REVEL	Benign	0.16
Sift	Benign	0.91	T;T
Sift4G	Benign	0.89	T;T
Polyphen		0.0020	B;.
Vest4		0.40
MutPred		0.43		Gain of disorder (P = 0.0019);Gain of disorder (P = 0.0019);
MVP		0.31
MPC		0.11
ClinPred		0.75	D
GERP RS		6.1
Varity_R		0.099
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00054
dbscSNV1_RF	Benign	0.012
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-73996856;