rs2277706

Variant names:

• chr17-81843795-T-G
• rs2277706
• NM_000918.4:c.*217A>C

Your query was ambiguous. Multiple possible variants found:

• chr17-81843795-T-G
• chr17-81843795-T-A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000918.4(P4HB):​c.*217A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0357 in 601,552 control chromosomes in the GnomAD database, including 1,452 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (541 hom., cov: 33)
  • Exomes 𝑓: 0.029 (911 hom.)
• Consequence: P4HB NM_000918.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.114
• Publications: 2 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 17-81843795-T-G is Benign according to our data. Variant chr17-81843795-T-G is described in ClinVar as Benign. ClinVar VariationId is 1178163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.164 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.*217A>C		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.*217A>C		3_prime_UTR	Exon 11 of 11	ENSP00000327801.4	P07237
	P4HB	ENST00000415593.6	TSL:1	c.*217A>C		3_prime_UTR	Exon 9 of 9	ENSP00000388117.2	H0Y3Z3
	P4HB	ENST00000473021.2	TSL:1	n.1384A>C		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.0549 AC: 8346 AN: 152102 Hom.: 541 Cov.: 33

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0856

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.175

Gnomad SAS AF: 0.0446

Gnomad FIN AF: 0.00386

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.00319

Gnomad OTH AF: 0.0416

GnomAD4 exome AF: 0.0292 AC: 13115 AN: 449332 Hom.: 911 Cov.: 0 AF XY: 0.0283 AC XY: 6713 AN XY: 237196

African (AFR) AF: 0.136 AC: 1701 AN: 12516

American (AMR) AF: 0.0961 AC: 1759 AN: 18302

Ashkenazi Jewish (ASJ) AF: 0.00690 AC: 94 AN: 13630

East Asian (EAS) AF: 0.192 AC: 5968 AN: 31070

South Asian (SAS) AF: 0.0368 AC: 1677 AN: 45558

European-Finnish (FIN) AF: 0.00576 AC: 171 AN: 29708

Middle Eastern (MID) AF: 0.0168 AC: 33 AN: 1968

European-Non Finnish (NFE) AF: 0.00364 AC: 986 AN: 270566

Other (OTH) AF: 0.0279 AC: 726 AN: 26014

GnomAD4 genome AF: 0.0549 AC: 8356 AN: 152220 Hom.: 541 Cov.: 33 AF XY: 0.0562 AC XY: 4185 AN XY: 74420

African (AFR) AF: 0.134 AC: 5557 AN: 41524

American (AMR) AF: 0.0856 AC: 1309 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.174 AC: 895 AN: 5146

South Asian (SAS) AF: 0.0449 AC: 216 AN: 4816

European-Finnish (FIN) AF: 0.00386 AC: 41 AN: 10616

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00319 AC: 217 AN: 68036

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

Alfa AF: 0.0469 Hom.: 259

Bravo AF: 0.0654

Asia WGS AF: 0.0890 AC: 310 AN: 3478

ClinVar

ClinVar submissions

Significance: 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	-0.42
CADD	Benign	11
DANN	Benign	0.78
PhyloP100		0.11
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: rs2277706; hg19: chr17-79801671; COSMIC: COSV107384628; COSMIC: COSV107384628;