rs2070872

Positions:

• chr17-81846845-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000918.4(P4HB):​c.855+102T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 1,449,520 control chromosomes in the GnomAD database, including 34,821 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5769 hom., cov: 33)
  • Exomes 𝑓: 0.20 (29052 hom.)
• Consequence: P4HB NM_000918.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.801

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 17-81846845-A-G is Benign according to our data. Variant chr17-81846845-A-G is described in ClinVar as [Benign]. Clinvar id is 1273968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.386 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
P4HB	NM_000918.4	c.855+102T>C		intron_variant		ENST00000331483.9	NP_000909.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
P4HB	ENST00000331483.9	c.855+102T>C		intron_variant		1	NM_000918.4	ENSP00000327801	P1

Frequencies

GnomAD3 genomes AF: 0.257 AC: 39041 AN: 151994 Hom.: 5753 Cov.: 33

Gnomad AFR AF: 0.391

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.303

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.285

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.171

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.214

GnomAD4 exome AF: 0.204 AC: 264892 AN: 1297406 Hom.: 29052 Cov.: 19 AF XY: 0.200 AC XY: 129960 AN XY: 649252

Gnomad4 AFR exome AF: 0.398

Gnomad4 AMR exome AF: 0.342

Gnomad4 ASJ exome AF: 0.144

Gnomad4 EAS exome AF: 0.308

Gnomad4 SAS exome AF: 0.138

Gnomad4 FIN exome AF: 0.171

Gnomad4 NFE exome AF: 0.197

Gnomad4 OTH exome AF: 0.204

GnomAD4 genome AF: 0.257 AC: 39093 AN: 152114 Hom.: 5769 Cov.: 33 AF XY: 0.255 AC XY: 18948 AN XY: 74380

Gnomad4 AFR AF: 0.391

Gnomad4 AMR AF: 0.302

Gnomad4 ASJ AF: 0.137

Gnomad4 EAS AF: 0.284

Gnomad4 SAS AF: 0.131

Gnomad4 FIN AF: 0.171

Gnomad4 NFE AF: 0.193

Gnomad4 OTH AF: 0.210

Alfa AF: 0.230 Hom.: 559

Bravo AF: 0.279

Asia WGS AF: 0.201 AC: 697 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.62
DANN	Benign	0.38

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: rs2070872; hg19: chr17-79804721; COSMIC: COSV58941351; COSMIC: COSV58941351;