17-81846845-A-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000918.4(P4HB):​c.855+102T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000077 in 1,298,844 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 33)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: P4HB NM_000918.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.801
• 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: 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.70e-7 AC: 1 AN: 1298844 Hom.: 0 Cov.: 19 AF XY: 0.00000154 AC XY: 1 AN XY: 649946

African (AFR) AF: 0.00 AC: 0 AN: 30302

American (AMR) AF: 0.00 AC: 0 AN: 42134

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23002

East Asian (EAS) AF: 0.00 AC: 0 AN: 38876

South Asian (SAS) AF: 0.0000128 AC: 1 AN: 77876

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 981112

Other (OTH) AF: 0.00 AC: 0 AN: 54698

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.58
DANN	Benign	0.53
PhyloP100		-0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;