rs1292724234

Variant names:

• chr14-77027414-G-A
• rs1292724234
• NM_024496.4:c.379C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-77027414-G-A
• chr14-77027414-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_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
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.62

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]

LOC107984638 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 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 11 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. Variant chr14-77027414-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF2BPL	NM_024496.4	c.379C>T	p.Gln127*	stop_gained	Exon 1 of 1	ENST00000238647.5	NP_078772.1
LOC107984638	NR_190000.1	n.-54G>A		upstream_gene_variant
LOC107984638	NR_190001.1	n.-54G>A		upstream_gene_variant
LOC107984638	NR_190002.1	n.-54G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF2BPL	ENST00000238647.5	c.379C>T	p.Gln127*	stop_gained	Exon 1 of 1	6	NM_024496.4	ENSP00000238647.3

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

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.: 30

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

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
Vest4		0.12
GERP RS		2.2

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: rs1292724234; hg19: chr14-77493757;