17-81845009-G-A

Variant names:

• chr17-81845009-G-A
• rs62077232
• NM_000918.4:c.1446+135C>T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000918.4(P4HB):​c.1446+135C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00592 in 723,730 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0057 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0060 (16 hom.)
• Consequence: P4HB NM_000918.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.593

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 17-81845009-G-A is Benign according to our data. Variant chr17-81845009-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3388119.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 861 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P4HB	NM_000918.4	c.1446+135C>T		intron_variant	Intron 10 of 10	ENST00000331483.9	NP_000909.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P4HB	ENST00000331483.9	c.1446+135C>T		intron_variant	Intron 10 of 10	1	NM_000918.4	ENSP00000327801.4

Frequencies

GnomAD3 genomes AF: 0.00566 AC: 861 AN: 152254 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0130

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00216

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00744

Gnomad OTH AF: 0.00621

GnomAD4 exome AF: 0.00599 AC: 3421 AN: 571358 Hom.: 16 AF XY: 0.00574 AC XY: 1715 AN XY: 298882

Gnomad4 AFR exome AF: 0.00175

Gnomad4 AMR exome AF: 0.00655

Gnomad4 ASJ exome AF: 0.0105

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000369

Gnomad4 FIN exome AF: 0.00191

Gnomad4 NFE exome AF: 0.00767

Gnomad4 OTH exome AF: 0.00695

GnomAD4 genome AF: 0.00565 AC: 861 AN: 152372 Hom.: 4 Cov.: 33 AF XY: 0.00540 AC XY: 402 AN XY: 74510

Gnomad4 AFR AF: 0.00200

Gnomad4 AMR AF: 0.0130

Gnomad4 ASJ AF: 0.00980

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00216

Gnomad4 NFE AF: 0.00744

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00545 Hom.: 0

Bravo AF: 0.00671

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

P4HB: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.29
DANN	Benign	0.74

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: rs62077232; hg19: chr17-79802885;