17-81843795-T-G

Position:

• chr17-81843795-T-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000918.4(P4HB):​c.*217A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0357 in 601,552 control chromosomes in the GnomAD database, including 1,452 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (541 hom., cov: 33)
  • Exomes 𝑓: 0.029 (911 hom.)
• Consequence: P4HB NM_000918.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.114

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 17-81843795-T-G is Benign according to our data. Variant chr17-81843795-T-G is described in ClinVar as [Benign]. Clinvar id is 1178163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
P4HB	NM_000918.4	c.*217A>C		3_prime_UTR_variant	11/11	ENST00000331483.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
P4HB	ENST00000331483.9	c.*217A>C		3_prime_UTR_variant	11/11	1	NM_000918.4	P1
	ENST00000576784.1	n.366T>G		non_coding_transcript_exon_variant	2/2	5

Frequencies

GnomAD3 genomes AF: 0.0549 AC: 8346 AN: 152102 Hom.: 541 Cov.: 33

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0856

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.175

Gnomad SAS AF: 0.0446

Gnomad FIN AF: 0.00386

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00319

Gnomad OTH AF: 0.0416

GnomAD4 exome AF: 0.0292 AC: 13115 AN: 449332 Hom.: 911 Cov.: 0 AF XY: 0.0283 AC XY: 6713 AN XY: 237196

Gnomad4 AFR exome AF: 0.136

Gnomad4 AMR exome AF: 0.0961

Gnomad4 ASJ exome AF: 0.00690

Gnomad4 EAS exome AF: 0.192

Gnomad4 SAS exome AF: 0.0368

Gnomad4 FIN exome AF: 0.00576

Gnomad4 NFE exome AF: 0.00364

Gnomad4 OTH exome AF: 0.0279

GnomAD4 genome AF: 0.0549 AC: 8356 AN: 152220 Hom.: 541 Cov.: 33 AF XY: 0.0562 AC XY: 4185 AN XY: 74420

Gnomad4 AFR AF: 0.134

Gnomad4 AMR AF: 0.0856

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.174

Gnomad4 SAS AF: 0.0449

Gnomad4 FIN AF: 0.00386

Gnomad4 NFE AF: 0.00319

Gnomad4 OTH AF: 0.0407

Alfa AF: 0.0195 Hom.: 42

Bravo AF: 0.0654

Asia WGS AF: 0.0890 AC: 310 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	Aug 20, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	11
DANN	Benign	0.78

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: rs2277706; hg19: chr17-79801671;