NM_000918.4:c.1446+135C>T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• 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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 3388119.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 861 AD gene.

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.1446+135C>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.1446+135C>T		intron	N/A	ENSP00000327801.4	P07237
	P4HB	ENST00000415593.6	TSL:1	c.1176+135C>T		intron	N/A	ENSP00000388117.2	H0Y3Z3
	P4HB	ENST00000473021.2	TSL:1	n.1086+135C>T		intron	N/A

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

African (AFR) AF: 0.00175 AC: 27 AN: 15472

American (AMR) AF: 0.00655 AC: 176 AN: 26884

Ashkenazi Jewish (ASJ) AF: 0.0105 AC: 168 AN: 16030

East Asian (EAS) AF: 0.00 AC: 0 AN: 31636

South Asian (SAS) AF: 0.0000369 AC: 2 AN: 54166

European-Finnish (FIN) AF: 0.00191 AC: 63 AN: 33028

Middle Eastern (MID) AF: 0.00117 AC: 3 AN: 2566

European-Non Finnish (NFE) AF: 0.00767 AC: 2772 AN: 361346

Other (OTH) AF: 0.00695 AC: 210 AN: 30230

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

African (AFR) AF: 0.00200 AC: 83 AN: 41594

American (AMR) AF: 0.0130 AC: 199 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00980 AC: 34 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00216 AC: 23 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00744 AC: 506 AN: 68032

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00545 Hom.: 0

Bravo AF: 0.00671

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely 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	-0.92
CADD	Benign	0.29
DANN	Benign	0.74
PhyloP100		-0.59
Mutation Taster		=100/0	polymorphism

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: rs62077232; hg19: chr17-79802885;