NM_000918.4:c.1447-9G>A

Variant names:

• chr17-81844101-C-T
• rs138348620
• NM_000918.4:c.1447-9G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000918.4(P4HB):​c.1447-9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0211 in 1,598,586 control chromosomes in the GnomAD database, including 2,127 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (533 hom., cov: 33)
  • Exomes 𝑓: 0.018 (1594 hom.)
• Consequence: P4HB NM_000918.4 intron
• Scores: Splicing: ADA: 0.0002609
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -5.67
• Publications: 3 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, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 17-81844101-C-T is Benign according to our data. Variant chr17-81844101-C-T is described in ClinVar as Benign. ClinVar VariationId is 1269426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.165 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.1447-9G>A		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.1447-9G>A		intron	N/A	ENSP00000327801.4	P07237
	P4HB	ENST00000415593.6	TSL:1	c.1177-9G>A		intron	N/A	ENSP00000388117.2	H0Y3Z3
	P4HB	ENST00000473021.2	TSL:1	n.1087-9G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0545 AC: 8287 AN: 152194 Hom.: 533 Cov.: 33

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0856

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.175

Gnomad SAS AF: 0.0459

Gnomad FIN AF: 0.00386

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00317

Gnomad OTH AF: 0.0416

GnomAD2 exomes AF: 0.0471 AC: 11832 AN: 251314 AF XY: 0.0409

Gnomad AFR exome AF: 0.136

Gnomad AMR exome AF: 0.125

Gnomad ASJ exome AF: 0.00754

Gnomad EAS exome AF: 0.179

Gnomad FIN exome AF: 0.00490

Gnomad NFE exome AF: 0.00383

Gnomad OTH exome AF: 0.0277

GnomAD4 exome AF: 0.0175 AC: 25373 AN: 1446274 Hom.: 1594 Cov.: 27 AF XY: 0.0172 AC XY: 12406 AN XY: 720516

African (AFR) AF: 0.139 AC: 4618 AN: 33110

American (AMR) AF: 0.117 AC: 5243 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00699 AC: 182 AN: 26044

East Asian (EAS) AF: 0.189 AC: 7501 AN: 39592

South Asian (SAS) AF: 0.0384 AC: 3299 AN: 85946

European-Finnish (FIN) AF: 0.00551 AC: 294 AN: 53316

Middle Eastern (MID) AF: 0.0193 AC: 110 AN: 5704

European-Non Finnish (NFE) AF: 0.00242 AC: 2657 AN: 1098082

Other (OTH) AF: 0.0246 AC: 1469 AN: 59786

GnomAD4 genome AF: 0.0545 AC: 8298 AN: 152312 Hom.: 533 Cov.: 33 AF XY: 0.0559 AC XY: 4165 AN XY: 74488

African (AFR) AF: 0.132 AC: 5484 AN: 41544

American (AMR) AF: 0.0856 AC: 1310 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.175 AC: 904 AN: 5180

South Asian (SAS) AF: 0.0461 AC: 223 AN: 4834

European-Finnish (FIN) AF: 0.00386 AC: 41 AN: 10632

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.00318 AC: 216 AN: 68028

Other (OTH) AF: 0.0407 AC: 86 AN: 2112

Alfa AF: 0.0228 Hom.: 80

Bravo AF: 0.0648

Asia WGS AF: 0.0910 AC: 315 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.77
DANN	Benign	0.88
PhyloP100		-5.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00026
dbscSNV1_RF	Benign	0.010
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: rs138348620; hg19: chr17-79801977; COSMIC: COSV58941288; COSMIC: COSV58941288;