Genetic Variant IRF2BPL:p.Glu172* (chr14-77027279-C-A) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_024496.4(IRF2BPL):c.514G>T(p.Glu172*) 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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 2.69

Publications

0 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 18 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 55 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 14-77027279-C-A is Pathogenic according to our data. Variant chr14-77027279-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 522821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF2BPL	NM_024496.4 link	c.514G>T	p.Glu172*	stop_gained	Exon 1 of 1	ENST00000238647.5	NP_078772.1	Q9H1B7
LOC107984638	NR_190000.1 link	n.-189C>A		upstream_gene_variant
LOC107984638	NR_190001.1 link	n.-189C>A		upstream_gene_variant
LOC107984638	NR_190002.1 link	n.-189C>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF2BPL	ENST00000238647.5 link	c.514G>T	p.Glu172*	stop_gained	Exon 1 of 1	6	NM_024496.4	ENSP00000238647.3		Q9H1B7
LINC02289	ENST00000716908.1 link	n.304+13775G>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:

1426254

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

709122

African (AFR)

AF:

0.00

AC:

AN:

30860

American (AMR)

AF:

0.00

AC:

AN:

38292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24148

East Asian (EAS)

AF:

0.00

AC:

AN:

37680

South Asian (SAS)

AF:

0.00

AC:

AN:

82730

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49436

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4748

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1099678

Other (OTH)

AF:

0.00

AC:

AN:

58682

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Jan 21, 2020

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation, as the last 625 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed in large population cohorts (Lek et al., 2016); Reported previously as a de novo change in an individual with an IRF2BPL-related disorder (Marcogliese et al., 2018); This variant is associated with the following publications: (PMID: 30057031) -

IRF2BPL-related disorder

Pathogenic:1

Aug 29, 2017

Undiagnosed Diseases Network, NIH

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

This individual has been reported in PMID: 30057031 (subject 1). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.73

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Benign

0.67

PhyloP100

2.7

Vest4

0.14

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

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