Genetic Variant NM_182972.3:c.116G>A (chr1-234609379-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_182972.3(IRF2BP2):c.116G>A(p.Gly39Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000661 in 151,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G39V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

IRF2BP2
NM_182972.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.98

Publications

0 publications found

Variant links:

COSMIC-nc: COSV64015760

Genes affected

IRF2BP2 (HGNC:21729): (interferon regulatory factor 2 binding protein 2) This gene encodes an interferon regulatory factor-2 (IRF2) binding protein that interacts with the C-terminal transcriptional repression domain of IRF2. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2008]

IRF2BP2 links:

LINC00184 (HGNC:37192): (long intergenic non-protein coding RNA 184)

LINC00184 links:

ENSG00000228830 (HGNC:):

ENSG00000228830 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.878

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF2BP2	NM_182972.3 link	c.116G>A	p.Gly39Asp	missense_variant	Exon 1 of 2	ENST00000366609.4	NP_892017.2	Q7Z5L9-1
IRF2BP2	NM_001077397.1 link	c.116G>A	p.Gly39Asp	missense_variant	Exon 1 of 2		NP_001070865.1	Q7Z5L9-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IRF2BP2	ENST00000366609.4 link	c.116G>A	p.Gly39Asp	missense_variant	Exon 1 of 2	1	NM_182972.3	ENSP00000355568.3	Q7Z5L9-1
IRF2BP2	ENST00000366610.8 link	c.116G>A	p.Gly39Asp	missense_variant	Exon 1 of 2	1		ENSP00000355569.3	Q7Z5L9-2
LINC00184	ENST00000796406.1 link	n.85C>T		non_coding_transcript_exon_variant	Exon 1 of 4
ENSG00000228830	ENST00000436039.1 link	n.631-42C>T		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

AF:

0.00000661

AC:

AN:

151368

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1405946

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

698054

African (AFR)

AF:

0.00

AC:

AN:

29048

American (AMR)

AF:

0.00

AC:

AN:

38828

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24676

East Asian (EAS)

AF:

0.00

AC:

AN:

33402

South Asian (SAS)

AF:

0.00

AC:

AN:

80360

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49974

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5178

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1086636

Other (OTH)

AF:

0.00

AC:

AN:

57844

GnomAD4 genome

AF:

0.00000661

AC:

AN:

151368

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

73928

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41350

American (AMR)

AF:

0.0000657

AC:

AN:

15210

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10244

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67812

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

.;T

Eigen

Benign

0.039

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.74

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.88

D;D

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

1.6

L;L

PhyloP100

3.0

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-5.6

D;D

REVEL

Uncertain

0.57

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.71

MutPred

0.64

Loss of catalytic residue at P35 (P = 0.1143);Loss of catalytic residue at P35 (P = 0.1143);

MVP

0.80

MPC

2.7

ClinPred

1.0

GERP RS

1.7

PromoterAI

0.017

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.9

Varity_R

0.93

gMVP

0.82

Mutation Taster

=36/64

disease causing

(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

Computational scores

Splicing

Publications

Other links and lift over