Genetic Variant IREB2:c.19+451C>T (chr15-78438807-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004136.4(IREB2):c.19+451C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 170,510 control chromosomes in the GnomAD database, including 6,123 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.23 ( 5418 hom., cov: 31)

Exomes 𝑓: 0.26 ( 705 hom. )

Consequence

IREB2
NM_004136.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0790

Publications

25 publications found

Variant links:

Genes affected

IREB2 (HGNC:6115): (iron responsive element binding protein 2) The protein encoded by this gene is an RNA-binding protein that acts to regulate iron levels in the cells by regulating the translation and stability of mRNAs that affect iron homeostasis under conditions when iron is depleted. When iron levels are low, this protein binds to iron-responsive elements (IRES), stem-loop structures located either in the 5' or 3' UTRs. Binding to the 5' UTR represses translation, while binding to the 3' UTR inhibits mRNA degradation. When iron is found in the cell, this protein is degraded in a F-box and leucine rich repeat protein 5-dependent manner. Variants in this gene have been associated with lung cancer and chronic obstructive pulmonary disease (COPD). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2017]

IREB2 Gene-Disease associations (from GenCC):

neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia
Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae)

IREB2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.76).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.336 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IREB2	NM_004136.4 link	c.19+451C>T		intron_variant	Intron 1 of 21	ENST00000258886.13	NP_004127.2	P48200-1D3DW85

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IREB2	ENST00000258886.13 link	c.19+451C>T		intron_variant	Intron 1 of 21	1	NM_004136.4	ENSP00000258886.8		P48200-1

Frequencies

GnomAD3 genomes

AF:

0.234

AC:

35480

AN:

151906

Hom.:

5416

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0560

Gnomad AMI

AF:

0.362

Gnomad AMR

AF:

0.222

Gnomad ASJ

AF:

0.345

Gnomad EAS

AF:

0.0392

Gnomad SAS

AF:

0.209

Gnomad FIN

AF:

0.313

Gnomad MID

AF:

0.361

Gnomad NFE

AF:

0.340

Gnomad OTH

AF:

0.256

GnomAD4 exome

AF:

0.258

AC:

4768

AN:

18486

Hom.:

705

Cov.:

AF XY:

0.251

AC XY:

2457

AN XY:

9788

show subpopulations

African (AFR)

AF:

0.0586

AC:

AN:

614

American (AMR)

AF:

0.174

AC:

146

AN:

840

Ashkenazi Jewish (ASJ)

AF:

0.350

AC:

211

AN:

602

East Asian (EAS)

AF:

0.0269

AC:

AN:

928

South Asian (SAS)

AF:

0.201

AC:

384

AN:

1914

European-Finnish (FIN)

AF:

0.273

AC:

208

AN:

762

Middle Eastern (MID)

AF:

0.360

AC:

AN:

European-Non Finnish (NFE)

AF:

0.298

AC:

3443

AN:

11552

Other (OTH)

AF:

0.239

AC:

284

AN:

1188

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

168

335

503

670

838

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.233

AC:

35486

AN:

152024

Hom.:

5418

Cov.:

AF XY:

0.231

AC XY:

17156

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.0558

AC:

2315

AN:

41516

American (AMR)

AF:

0.221

AC:

3379

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.345

AC:

1197

AN:

3470

East Asian (EAS)

AF:

0.0394

AC:

204

AN:

5172

South Asian (SAS)

AF:

0.212

AC:

1019

AN:

4816

European-Finnish (FIN)

AF:

0.313

AC:

3306

AN:

10552

Middle Eastern (MID)

AF:

0.364

AC:

107

AN:

294

European-Non Finnish (NFE)

AF:

0.340

AC:

23093

AN:

67910

Other (OTH)

AF:

0.254

AC:

536

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1277

2554

3831

5108

6385

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

356

712

1068

1424

1780

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.274

Hom.:

3159

Bravo

AF:

0.218

Asia WGS

AF:

0.126

AC:

439

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.76

CADD

Benign

6.8

(source)

DANN

Benign

0.79

PhyloP100

-0.079

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over