rs2070872

Variant names:

• chr17-81846845-A-G
• rs2070872
• NM_000918.4:c.855+102T>C

Your query was ambiguous. Multiple possible variants found:

• chr17-81846845-A-G
• chr17-81846845-A-T

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.855+102T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 1,449,520 control chromosomes in the GnomAD database, including 34,821 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5769 hom., cov: 33)
  • Exomes 𝑓: 0.20 (29052 hom.)
• Consequence: P4HB NM_000918.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.801
• Publications: 7 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, G2P, PanelApp Australia, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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=-0.91).
• BP6: Variant 17-81846845-A-G is Benign according to our data. Variant chr17-81846845-A-G is described in ClinVar as Benign. ClinVar VariationId is 1273968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.386 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P4HB	NM_000918.4	c.855+102T>C		intron_variant	Intron 6 of 10	ENST00000331483.9	NP_000909.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P4HB	ENST00000331483.9	c.855+102T>C		intron_variant	Intron 6 of 10	1	NM_000918.4	ENSP00000327801.4

Frequencies

GnomAD3 genomes AF: 0.257 AC: 39041 AN: 151994 Hom.: 5753 Cov.: 33

Gnomad AFR AF: 0.391

Gnomad AMI AF: 0.287

Gnomad AMR AF: 0.303

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.285

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.171

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.214

GnomAD4 exome AF: 0.204 AC: 264892 AN: 1297406 Hom.: 29052 Cov.: 19 AF XY: 0.200 AC XY: 129960 AN XY: 649252

African (AFR) AF: 0.398 AC: 12044 AN: 30248

American (AMR) AF: 0.342 AC: 14409 AN: 42106

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 3300 AN: 22986

East Asian (EAS) AF: 0.308 AC: 11980 AN: 38866

South Asian (SAS) AF: 0.138 AC: 10777 AN: 77844

European-Finnish (FIN) AF: 0.171 AC: 8071 AN: 47070

Middle Eastern (MID) AF: 0.121 AC: 455 AN: 3752

European-Non Finnish (NFE) AF: 0.197 AC: 192685 AN: 979882

Other (OTH) AF: 0.204 AC: 11171 AN: 54652

GnomAD4 genome AF: 0.257 AC: 39093 AN: 152114 Hom.: 5769 Cov.: 33 AF XY: 0.255 AC XY: 18948 AN XY: 74380

African (AFR) AF: 0.391 AC: 16211 AN: 41472

American (AMR) AF: 0.302 AC: 4618 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 477 AN: 3472

East Asian (EAS) AF: 0.284 AC: 1467 AN: 5166

South Asian (SAS) AF: 0.131 AC: 633 AN: 4822

European-Finnish (FIN) AF: 0.171 AC: 1817 AN: 10604

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.193 AC: 13131 AN: 67982

Other (OTH) AF: 0.210 AC: 444 AN: 2110

Alfa AF: 0.230 Hom.: 559

Bravo AF: 0.279

Asia WGS AF: 0.201 AC: 697 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 31, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.62
DANN	Benign	0.38
PhyloP100		-0.80
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: rs2070872; hg19: chr17-79804721; COSMIC: COSV58941351; COSMIC: COSV58941351;