rs112897683

Variant names:

• chr17-81844179-G-A
• rs112897683
• NM_000918.4:c.1447-87C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000918.4(P4HB):​c.1447-87C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00708 in 956,842 control chromosomes in the GnomAD database, including 292 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.027 (191 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (101 hom.)
• Consequence: P4HB NM_000918.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.440
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, PanelApp Australia, Genomics England PanelApp
• Cole-Carpenter syndrome

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

P4HB-AS1 (HGNC:58201):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 17-81844179-G-A is Benign according to our data. Variant chr17-81844179-G-A is described in ClinVar as Benign. ClinVar VariationId is 1272512.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0918 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P4HB	NM_000918.4	MANE Select	c.1447-87C>T		intron	N/A	NP_000909.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P4HB	ENST00000331483.9	TSL:1 MANE Select	c.1447-87C>T		intron	N/A	ENSP00000327801.4	P07237
	P4HB	ENST00000415593.6	TSL:1	c.1177-87C>T		intron	N/A	ENSP00000388117.2	H0Y3Z3
	P4HB	ENST00000473021.2	TSL:1	n.1087-87C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0271 AC: 4120 AN: 152168 Hom.: 188 Cov.: 33

Gnomad AFR AF: 0.0942

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00923

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0196

GnomAD4 exome AF: 0.00329 AC: 2645 AN: 804556 Hom.: 101 AF XY: 0.00269 AC XY: 1144 AN XY: 425878

African (AFR) AF: 0.0937 AC: 1929 AN: 20580

American (AMR) AF: 0.00544 AC: 237 AN: 43562

Ashkenazi Jewish (ASJ) AF: 0.00382 AC: 84 AN: 21968

East Asian (EAS) AF: 0.0000272 AC: 1 AN: 36780

South Asian (SAS) AF: 0.000260 AC: 19 AN: 73016

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49550

Middle Eastern (MID) AF: 0.00461 AC: 15 AN: 3254

European-Non Finnish (NFE) AF: 0.000164 AC: 85 AN: 516972

Other (OTH) AF: 0.00707 AC: 275 AN: 38874

GnomAD4 genome AF: 0.0271 AC: 4133 AN: 152286 Hom.: 191 Cov.: 33 AF XY: 0.0260 AC XY: 1935 AN XY: 74472

African (AFR) AF: 0.0942 AC: 3916 AN: 41556

American (AMR) AF: 0.00922 AC: 141 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68004

Other (OTH) AF: 0.0194 AC: 41 AN: 2112

Alfa AF: 0.0158 Hom.: 16

Bravo AF: 0.0312

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.53
DANN	Benign	0.75
PhyloP100		-0.44
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs112897683; hg19: chr17-79802055;