chr17-81843412-C-A

Variant names:

• chr17-81843412-C-A
• rs8324
• NM_000918.4:c.*600G>T

Variant summary

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

The NM_000918.4(P4HB):​c.*600G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 399,174 control chromosomes in the GnomAD database, including 8,300 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 0.19 (3048 hom., cov: 33)
  • Exomes 𝑓: 0.20 (5252 hom.)
• Consequence: P4HB NM_000918.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00600
• Publications: 12 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.272 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.*600G>T		3_prime_UTR	Exon 11 of 11	NP_000909.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P4HB	ENST00000331483.9	TSL:1 MANE Select	c.*600G>T		3_prime_UTR	Exon 11 of 11	ENSP00000327801.4	P07237
	P4HB	ENST00000415593.6	TSL:1	c.*600G>T		3_prime_UTR	Exon 9 of 9	ENSP00000388117.2	H0Y3Z3
	P4HB	ENST00000473021.2	TSL:1	n.1767G>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.193 AC: 29316 AN: 151956 Hom.: 3049 Cov.: 33

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.280

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.280

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.170

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.167

GnomAD4 exome AF: 0.200 AC: 49377 AN: 247098 Hom.: 5252 Cov.: 0 AF XY: 0.199 AC XY: 24875 AN XY: 125242

African (AFR) AF: 0.173 AC: 1239 AN: 7170

American (AMR) AF: 0.303 AC: 2319 AN: 7652

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 1314 AN: 9212

East Asian (EAS) AF: 0.317 AC: 7242 AN: 22876

South Asian (SAS) AF: 0.134 AC: 381 AN: 2844

European-Finnish (FIN) AF: 0.174 AC: 3605 AN: 20734

Middle Eastern (MID) AF: 0.0995 AC: 128 AN: 1286

European-Non Finnish (NFE) AF: 0.189 AC: 30032 AN: 158960

Other (OTH) AF: 0.190 AC: 3117 AN: 16364

GnomAD4 genome AF: 0.193 AC: 29322 AN: 152076 Hom.: 3048 Cov.: 33 AF XY: 0.193 AC XY: 14334 AN XY: 74362

African (AFR) AF: 0.169 AC: 7002 AN: 41498

American (AMR) AF: 0.279 AC: 4272 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 469 AN: 3470

East Asian (EAS) AF: 0.279 AC: 1437 AN: 5144

South Asian (SAS) AF: 0.131 AC: 632 AN: 4826

European-Finnish (FIN) AF: 0.170 AC: 1806 AN: 10598

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.192 AC: 13066 AN: 67940

Other (OTH) AF: 0.164 AC: 347 AN: 2110

Alfa AF: 0.191 Hom.: 360

Bravo AF: 0.205

Asia WGS AF: 0.182 AC: 630 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.9
DANN	Benign	0.62
PhyloP100		0.0060
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: rs8324; hg19: chr17-79801288; COSMIC: COSV107384627; COSMIC: COSV107384627;