rs17484524

Variant names:

• chr15-78480334-A-G
• rs17484524
• NM_004136.4:c.1296+1937A>G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004136.4(IREB2):​c.1296+1937A>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 152,176 control chromosomes in the GnomAD database, including 5,434 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 (5434 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: IREB2 NM_004136.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.92

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]

ENSG00000259474 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• 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.1296+1937A>G		intron_variant	Intron 10 of 21	ENST00000258886.13	NP_004127.2
IREB2	NM_001320942.2	c.1125+1937A>G		intron_variant	Intron 10 of 21		NP_001307871.2
IREB2	NM_001354994.2	c.1125+1937A>G		intron_variant	Intron 10 of 21		NP_001341923.2
IREB2	NM_001320941.2	c.546+1937A>G		intron_variant	Intron 9 of 20		NP_001307870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IREB2	ENST00000258886.13	c.1296+1937A>G		intron_variant	Intron 10 of 21	1	NM_004136.4	ENSP00000258886.8
IREB2	ENST00000558570.5	n.*563+1937A>G		intron_variant	Intron 9 of 20	1		ENSP00000454063.1
ENSG00000259474	ENST00000560094.1	n.122-74T>C		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35564 AN: 152058 Hom.: 5432 Cov.: 32

Gnomad AFR AF: 0.0562

Gnomad AMI AF: 0.363

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.352

Gnomad EAS AF: 0.0398

Gnomad SAS AF: 0.203

Gnomad FIN AF: 0.313

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.257

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 4 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.234 AC: 35570 AN: 152176 Hom.: 5434 Cov.: 32 AF XY: 0.231 AC XY: 17173 AN XY: 74382

Gnomad4 AFR AF: 0.0561

Gnomad4 AMR AF: 0.222

Gnomad4 ASJ AF: 0.352

Gnomad4 EAS AF: 0.0401

Gnomad4 SAS AF: 0.205

Gnomad4 FIN AF: 0.313

Gnomad4 NFE AF: 0.341

Gnomad4 OTH AF: 0.255

Alfa AF: 0.302 Hom.: 1735

Bravo AF: 0.218

Asia WGS AF: 0.123 AC: 430 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.0
DANN	Benign	0.40

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

LitVar

Other links and lift over

dbSNP: rs17484524; hg19: chr15-78772676;