rs1345176461

Positions:

• chr14-77027231-G-A
• chr14-77027231-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_024496.4(IRF2BPL):​c.562C>T​(p.Arg188Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: IRF2BPL NM_024496.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 0.947

Genes affected

IRF2BPL (HGNC:14282): (interferon regulatory factor 2 binding protein like) This gene encodes a transcription factor that may play a role in regulating female reproductive function. [provided by RefSeq, Jun 2012]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-77027231-G-A is Pathogenic according to our data. Variant chr14-77027231-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 559608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-77027231-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IRF2BPL	NM_024496.4	c.562C>T	p.Arg188Ter	stop_gained	1/1	ENST00000238647.5	NP_078772.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IRF2BPL	ENST00000238647.5	c.562C>T	p.Arg188Ter	stop_gained	1/1		NM_024496.4	ENSP00000238647	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000433 AC: 1 AN: 230838 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 126272

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000977

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1449506 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 720854

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 20, 2018	- -
Pathogenic, criteria provided, single submitter	research	Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL)	Apr 27, 2023	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 01, 2018

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 02, 2019

DNA sequence analysis of the IRF2BPL gene demonstrated a pathogenic sequence change, c.562C>T, which results in the creation of a premature stop codon at amino acid position 188, p.Arg188*. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated IRF2BPL protein with potentially abnormal function. This variant is absent from the ExAC population database. This particular sequence change has previously been described in the heterozygous state in two patients with movement abnormalities including dystonia and ataxia, and was confirmed de novo in one of the two patients (Marcogliese et. al., 2018). Patients with nonsense variants in this gene were reported to have a clinical course that included loss of developmental milestones, and onset of seizure disorders at variable ages, and movement disorders with dystonia, choreoathetosis, and cerebellar signs such as ataxia, and dysarthria. (Marcogliese et. al., 2018). Subsequent targeted sequence analysis demonstrated the absence of the c.562C>T sequence change in parents. Therefore the c.562C>T sequence change appears to be a de novo event in this case. -

IRF2BPL-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Undiagnosed Diseases Network, NIH

Oct 30, 2017

This individual has been reported in PMID: 30057031 (subject 3). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.58	D
MutationTaster	Benign	1.0	D
Vest4		0.14
GERP RS		2.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs1345176461; hg19: chr14-77493574;