dbSNP rs3743079: IREB2:c.*576C>T (chr15-78498719-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.*576C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.151 in 152,480 control chromosomes in the GnomAD database, including 1,784 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 0.15 ( 1779 hom., cov: 33)

Exomes 𝑓: 0.14 ( 5 hom. )

Consequence

IREB2
NM_004136.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.612

Publications

20 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:

Genome browser will be placed here

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=-0.75).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
IREB2	NM_004136.4 link	c.*576C>T	3_prime_UTR_variant	Exon 22 of 22	ENST00000258886.13	NP_004127.2
IREB2	NM_001320942.2 link	c.*576C>T	3_prime_UTR_variant	Exon 22 of 22		NP_001307871.2
IREB2	NM_001354994.2 link	c.*576C>T	3_prime_UTR_variant	Exon 22 of 22		NP_001341923.2
IREB2	NM_001320941.2 link	c.*576C>T	3_prime_UTR_variant	Exon 21 of 21		NP_001307870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IREB2	ENST00000258886.13 link	c.*576C>T		3_prime_UTR_variant	Exon 22 of 22	1	NM_004136.4	ENSP00000258886.8

Frequencies

GnomAD3 genomes

AF:

0.151

AC:

23003

AN:

152060

Hom.:

1772

Cov.:

show subpopulations

Gnomad AFR

AF:

0.142

Gnomad AMI

AF:

0.157

Gnomad AMR

AF:

0.111

Gnomad ASJ

AF:

0.204

Gnomad EAS

AF:

0.148

Gnomad SAS

AF:

0.160

Gnomad FIN

AF:

0.164

Gnomad MID

AF:

0.117

Gnomad NFE

AF:

0.161

Gnomad OTH

AF:

0.159

GnomAD4 exome

AF:

0.136

AC:

AN:

302

Hom.:

Cov.:

AF XY:

0.149

AC XY:

AN XY:

194

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.108

AC:

AN:

222

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.229

AC:

AN:

Other (OTH)

AF:

0.250

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.540

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.151

AC:

23039

AN:

152178

Hom.:

1779

Cov.:

AF XY:

0.151

AC XY:

11251

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.142

AC:

5909

AN:

41520

American (AMR)

AF:

0.110

AC:

1686

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.204

AC:

710

AN:

3472

East Asian (EAS)

AF:

0.148

AC:

766

AN:

5178

South Asian (SAS)

AF:

0.161

AC:

774

AN:

4822

European-Finnish (FIN)

AF:

0.164

AC:

1731

AN:

10578

Middle Eastern (MID)

AF:

0.119

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.161

AC:

10937

AN:

68004

Other (OTH)

AF:

0.165

AC:

348

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1004

2007

3011

4014

5018

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

264

528

792

1056

1320

<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:

0.159

Hom.:

7660

Bravo

AF:

0.148

Asia WGS

AF:

0.167

AC:

580

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

6.8

(source)

DANN

Benign

0.69

PhyloP100

0.61

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over