Genetic Variant NM_024496.4:c.379C>T (chr14-77027414-G-A) – ACMG Classification: Pathogenic (12 pts)

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

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]

IRF2BPL links:

LINC02289 (HGNC:53205): (long intergenic non-protein coding RNA 2289)

LINC02289 links:

LOC107984638 (HGNC:):

LOC107984638 links:

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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
IRF2BPL	NM_024496.4 link	c.379C>T	p.Gln127*	stop_gained	Exon 1 of 1	ENST00000238647.5	NP_078772.1	Q9H1B7
LOC107984638	NR_190000.1 link	n.-54G>A		upstream_gene_variant
LOC107984638	NR_190001.1 link	n.-54G>A		upstream_gene_variant
LOC107984638	NR_190002.1 link	n.-54G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF2BPL	ENST00000238647.5 link	c.379C>T	p.Gln127*	stop_gained	Exon 1 of 1	6	NM_024496.4	ENSP00000238647.3		Q9H1B7
LINC02289	ENST00000716908.1 link	n.304+13640C>T		intron_variant	Intron 2 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1331536

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

656920

African (AFR)

AF:

0.00

AC:

AN:

26738

American (AMR)

AF:

0.00

AC:

AN:

28024

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23136

East Asian (EAS)

AF:

0.00

AC:

AN:

29270

South Asian (SAS)

AF:

0.00

AC:

AN:

73310

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4120

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1047026

Other (OTH)

AF:

0.00

AC:

AN:

54556

GnomAD4 genome

Cov.:

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

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.36

Eigen_PC

Benign

0.088

FATHMM_MKL

Benign

0.49

PhyloP100

2.6

Vest4

0.12

GERP RS

2.2

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over