rs876016

chr17-81852587-A-Gchr17-81852587-A-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000918.4(P4HB):c.624+2555T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.228 in 152,232 control chromosomes in the GnomAD database, including 4,235 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.23 (4235 hom., cov: 33)
• Consequence: P4HB NM_000918.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.92

Genes affected

P4HB (HGNC:8548): (prolyl 4-hydroxylase subunit beta) This gene encodes the beta subunit of prolyl 4-hydroxylase, a highly abundant multifunctional enzyme that belongs to the protein disulfide isomerase family. When present as a tetramer consisting of two alpha and two beta subunits, this enzyme is involved in hydroxylation of prolyl residues in preprocollagen. This enzyme is also a disulfide isomerase containing two thioredoxin domains that catalyze the formation, breakage and rearrangement of disulfide bonds. Other known functions include its ability to act as a chaperone that inhibits aggregation of misfolded proteins in a concentration-dependent manner, its ability to bind thyroid hormone, its role in both the influx and efflux of S-nitrosothiol-bound nitric oxide, and its function as a subunit of the microsomal triglyceride transfer protein complex. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
P4HB	NM_000918.4	c.624+2555T>C		intron_variant		ENST00000331483.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
P4HB	ENST00000331483.9	c.624+2555T>C		intron_variant		1	NM_000918.4	P1

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34717 AN: 152112 Hom.: 4232 Cov.: 33

Gnomad AFR AF: 0.281

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.294

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.283

Gnomad SAS AF: 0.141

Gnomad FIN AF: 0.174

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.194

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

GnomAD4 genome AF: 0.228 AC: 34742 AN: 152232 Hom.: 4235 Cov.: 33 AF XY: 0.227 AC XY: 16883 AN XY: 74436

Gnomad4 AFR AF: 0.281

Gnomad4 AMR AF: 0.294

Gnomad4 ASJ AF: 0.139

Gnomad4 EAS AF: 0.282

Gnomad4 SAS AF: 0.141

Gnomad4 FIN AF: 0.174

Gnomad4 NFE AF: 0.197

Gnomad4 OTH AF: 0.191

Alfa AF: 0.227 Hom.: 1321

Bravo AF: 0.245

Asia WGS AF: 0.199 AC: 692 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
Cadd	Benign	0.95
Dann	Benign	0.48

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

Publications

LitVar

Other links and lift over

dbSNP: rs876016; hg19: chr17-79810463;