14-77025655-AG-A

Position:

• chr14-77025655-AG-A

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.2137del​(p.Leu713SerfsTer54) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IRF2BPL NM_024496.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.28

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. Fraction of 0.106 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-77025655-AG-A is Pathogenic according to our data. Variant chr14-77025655-AG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1691661.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IRF2BPL	NM_024496.4	c.2137del	p.Leu713SerfsTer54	frameshift_variant	1/1	ENST00000238647.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IRF2BPL	ENST00000238647.5	c.2137del	p.Leu713SerfsTer54	frameshift_variant	1/1		NM_024496.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Aug 25, 2022

The heterozygous p.Leu713fs variant in IRF2BPL was identified in 1 individual with a neurodevelopmental disorder including absent speech, seizure, global developmental delay, dystonia, athetosis, and abnormal social behavior via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Neurodev Study (https://www.neurodevproject.org/). Trio exome analysis showed this variant to be de novo. The p.Leu713fs variant in IRF2BPL has not been previously reported in individuals with a neurodevelopmental disorder and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 713 and leads to a premature termination codon 54 amino acids downstream. This gene is a single exon gene so frameshift variants are more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. However, this variant is predicted to remove >10% of the normal protein sequence, and is therefore likely to disrupt protein function. Heterozygous loss of function of the IRF2BPL gene is an established disease mechanism in neurodevelopmental disorders. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant neurodevelopmental disorder. ACMG/AMP Criteria applied: PVS1_strong, PS2_moderate, PM2_supporting (Richards 2015). -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 07, 2021

Frameshift variant predicted to result in protein truncation, as the last 84 amino acids are replaced with 53 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

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: rs1885090179; hg19: chr14-77491998;