17-81845068-G-C

Variant names:

• chr17-81845068-G-C
• rs74006119
• NM_000918.4:c.1446+76C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000918.4(P4HB):​c.1446+76C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00143 in 1,223,586 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (4 hom., cov: 33)
  • Exomes 𝑓: 0.00075 (3 hom.)
• Consequence: P4HB NM_000918.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.395
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 17-81845068-G-C is Benign according to our data. Variant chr17-81845068-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1205114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00618 (941/152340) while in subpopulation AFR AF = 0.0208 (867/41584). AF 95% confidence interval is 0.0197. There are 4 homozygotes in GnomAd4. There are 460 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 941 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+76C>G		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+76C>G		intron	N/A	ENSP00000327801.4	P07237
	P4HB	ENST00000415593.6	TSL:1	c.1176+76C>G		intron	N/A	ENSP00000388117.2	H0Y3Z3
	P4HB	ENST00000473021.2	TSL:1	n.1086+76C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00612 AC: 932 AN: 152222 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0207

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00718

GnomAD4 exome AF: 0.000751 AC: 805 AN: 1071246 Hom.: 3 AF XY: 0.000660 AC XY: 358 AN XY: 542590

African (AFR) AF: 0.0231 AC: 592 AN: 25628

American (AMR) AF: 0.00188 AC: 70 AN: 37304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22970

East Asian (EAS) AF: 0.00 AC: 0 AN: 35986

South Asian (SAS) AF: 0.0000541 AC: 4 AN: 73954

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47702

Middle Eastern (MID) AF: 0.000997 AC: 5 AN: 5014

European-Non Finnish (NFE) AF: 0.0000761 AC: 59 AN: 775618

Other (OTH) AF: 0.00159 AC: 75 AN: 47070

GnomAD4 genome AF: 0.00618 AC: 941 AN: 152340 Hom.: 4 Cov.: 33 AF XY: 0.00617 AC XY: 460 AN XY: 74498

African (AFR) AF: 0.0208 AC: 867 AN: 41584

American (AMR) AF: 0.00333 AC: 51 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68028

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.000140 Hom.: 0

Bravo AF: 0.00739

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.46
DANN	Benign	0.35
PhyloP100		-0.40
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs74006119; hg19: chr17-79802944;