15-78469072-C-G

Variant names:

• chr15-78469072-C-G
• rs17484235
• NM_004136.4:c.630-1460C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004136.4(IREB2):​c.630-1460C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 151,978 control chromosomes in the GnomAD database, including 5,424 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 (5424 hom., cov: 32)
• Consequence: IREB2 NM_004136.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.477
• Publications: 18 publications found

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)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.337 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IREB2	NM_004136.4	c.630-1460C>G		intron_variant	Intron 5 of 21	ENST00000258886.13	NP_004127.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IREB2	ENST00000258886.13	c.630-1460C>G		intron_variant	Intron 5 of 21	1	NM_004136.4	ENSP00000258886.8

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35518 AN: 151860 Hom.: 5422 Cov.: 32

Gnomad AFR AF: 0.0562

Gnomad AMI AF: 0.362

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.345

Gnomad EAS AF: 0.0397

Gnomad SAS AF: 0.204

Gnomad FIN AF: 0.314

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.257

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.234 AC: 35524 AN: 151978 Hom.: 5424 Cov.: 32 AF XY: 0.231 AC XY: 17170 AN XY: 74276

African (AFR) AF: 0.0560 AC: 2321 AN: 41460

American (AMR) AF: 0.221 AC: 3375 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 1196 AN: 3468

East Asian (EAS) AF: 0.0400 AC: 207 AN: 5174

South Asian (SAS) AF: 0.206 AC: 990 AN: 4810

European-Finnish (FIN) AF: 0.314 AC: 3308 AN: 10530

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.341 AC: 23149 AN: 67964

Other (OTH) AF: 0.256 AC: 540 AN: 2112

Alfa AF: 0.157 Hom.: 337

Bravo AF: 0.218

Asia WGS AF: 0.122 AC: 428 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.95
DANN	Benign	0.62
PhyloP100		-0.48
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17484235; hg19: chr15-78761414;