17-81852766-A-G

Variant names:

• chr17-81852766-A-G
• rs876017
• NM_000918.4:c.624+2376T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000918.4(P4HB):​c.624+2376T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 152,228 control chromosomes in the GnomAD database, including 4,340 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 (4340 hom., cov: 33)
• Consequence: P4HB NM_000918.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.966
• Publications: 4 publications found

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]

P4HB Gene-Disease associations (from GenCC):

• Cole-Carpenter syndrome 1

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Cole-Carpenter syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• osteogenesis imperfecta type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.288 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000918.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P4HB	NM_000918.4	MANE Select	c.624+2376T>C		intron	N/A	NP_000909.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P4HB	ENST00000331483.9	TSL:1 MANE Select	c.624+2376T>C		intron	N/A	ENSP00000327801.4
	P4HB	ENST00000415593.6	TSL:1	c.355-5419T>C		intron	N/A	ENSP00000388117.2
	P4HB	ENST00000477607.7	TSL:1	n.816+2376T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.231 AC: 35135 AN: 152110 Hom.: 4337 Cov.: 33

Gnomad AFR AF: 0.289

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.139

Gnomad EAS AF: 0.290

Gnomad SAS AF: 0.144

Gnomad FIN AF: 0.174

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.197

Gnomad OTH AF: 0.196

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

GnomAD4 genome AF: 0.231 AC: 35162 AN: 152228 Hom.: 4340 Cov.: 33 AF XY: 0.230 AC XY: 17095 AN XY: 74444

African (AFR) AF: 0.289 AC: 12002 AN: 41530

American (AMR) AF: 0.295 AC: 4516 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 482 AN: 3472

East Asian (EAS) AF: 0.289 AC: 1497 AN: 5182

South Asian (SAS) AF: 0.144 AC: 694 AN: 4830

European-Finnish (FIN) AF: 0.174 AC: 1844 AN: 10608

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.197 AC: 13419 AN: 68000

Other (OTH) AF: 0.193 AC: 407 AN: 2110

Alfa AF: 0.216 Hom.: 567

Bravo AF: 0.248

Asia WGS AF: 0.202 AC: 700 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.38
DANN	Benign	0.19
PhyloP100		-0.97
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs876017; hg19: chr17-79810642;