NM_024496.4:c.379C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_024496.4(IRF2BPL):​c.379C>T​(p.Gln127*) 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: 30)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

IRF2BPL
NM_024496.4 stop_gained

Scores

2
2
3

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 2.62

Publications

1 publications found
Variant links:
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]
LINC02289 (HGNC:53205): (long intergenic non-protein coding RNA 2289)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 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 63 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 14-77027414-G-A is Pathogenic according to our data. Variant chr14-77027414-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 559609.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IRF2BPLNM_024496.4 linkc.379C>T p.Gln127* stop_gained Exon 1 of 1 ENST00000238647.5 NP_078772.1 Q9H1B7
LOC107984638NR_190000.1 linkn.-54G>A upstream_gene_variant
LOC107984638NR_190001.1 linkn.-54G>A upstream_gene_variant
LOC107984638NR_190002.1 linkn.-54G>A upstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IRF2BPLENST00000238647.5 linkc.379C>T p.Gln127* stop_gained Exon 1 of 1 6 NM_024496.4 ENSP00000238647.3 Q9H1B7
LINC02289ENST00000716908.1 linkn.304+13640C>T intron_variant Intron 2 of 2

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1331536
Hom.:
0
Cov.:
63
AF XY:
0.00
AC XY:
0
AN XY:
656920
African (AFR)
AF:
0.00
AC:
0
AN:
26738
American (AMR)
AF:
0.00
AC:
0
AN:
28024
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
23136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
29270
South Asian (SAS)
AF:
0.00
AC:
0
AN:
73310
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
45356
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4120
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1047026
Other (OTH)
AF:
0.00
AC:
0
AN:
54556
GnomAD4 genome
Cov.:
30

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures Pathogenic:2
Jun 08, 2019
New York Genome Center
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.379C>T (p.Gln127Ter) variant identified in the IRF2BPL gene leads to the premature termination of the protein at amino acid 127/797 (coding exon 1/1). This variant is absent from gnomAD and ExAC, suggesting it is not a common benign variant in the populations represented in these databases. It is reported as Pathogenic in ClinVar (VarID: 559609), and has been previously identified in a 16y female with global developmental delay, hypotonia, seizures, gait abnormalities with wheelchair dependence, and regession of gross and fine motor and speech abilities beginning at approximately 12 years of age [PMID: 30057031]. Given the deleterious nature of the c.379C>T (p.Gln127Ter) variant, its absence in population databases, and its previous report in a similarly affected individual, it is reported here as Likely Pathogenic. -

Dec 20, 2018
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.48
D
BayesDel_noAF
Pathogenic
0.44
CADD
Pathogenic
37
DANN
Uncertain
1.0
Eigen
Uncertain
0.36
Eigen_PC
Benign
0.088
FATHMM_MKL
Benign
0.49
N
PhyloP100
2.6
Vest4
0.12
GERP RS
2.2
Mutation Taster
=1/199
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1292724234; hg19: chr14-77493757; API