rs8043227

Positions:

• chr15-78476529-C-G

Variant summary

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

The NM_001320943.2(IREB2):​c.*3139C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.547 in 470,970 control chromosomes in the GnomAD database, including 73,775 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 0.51 (20888 hom., cov: 32)
  • Exomes 𝑓: 0.57 (52887 hom.)
• Consequence: IREB2 NM_001320943.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0790

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.614 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IREB2	NM_004136.4	c.1195+170C>G		intron_variant		ENST00000258886.13	NP_004127.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IREB2	ENST00000560440.5	c.*3139C>G		3_prime_UTR_variant	8/8	1		ENSP00000452938.1
IREB2	ENST00000258886.13	c.1195+170C>G		intron_variant		1	NM_004136.4	ENSP00000258886.8
IREB2	ENST00000558570.5	n.*462+170C>G		intron_variant		1		ENSP00000454063.1

Frequencies

GnomAD3 genomes AF: 0.506 AC: 76962 AN: 151950 Hom.: 20876 Cov.: 32

Gnomad AFR AF: 0.305

Gnomad AMI AF: 0.687

Gnomad AMR AF: 0.498

Gnomad ASJ AF: 0.554

Gnomad EAS AF: 0.464

Gnomad SAS AF: 0.480

Gnomad FIN AF: 0.587

Gnomad MID AF: 0.548

Gnomad NFE AF: 0.619

Gnomad OTH AF: 0.518

GnomAD4 exome AF: 0.567 AC: 180771 AN: 318902 Hom.: 52887 Cov.: 5 AF XY: 0.565 AC XY: 93265 AN XY: 164972

Gnomad4 AFR exome AF: 0.291

Gnomad4 AMR exome AF: 0.490

Gnomad4 ASJ exome AF: 0.526

Gnomad4 EAS exome AF: 0.429

Gnomad4 SAS exome AF: 0.460

Gnomad4 FIN exome AF: 0.587

Gnomad4 NFE exome AF: 0.617

Gnomad4 OTH exome AF: 0.540

GnomAD4 genome AF: 0.506 AC: 76996 AN: 152068 Hom.: 20888 Cov.: 32 AF XY: 0.506 AC XY: 37621 AN XY: 74320

Gnomad4 AFR AF: 0.305

Gnomad4 AMR AF: 0.497

Gnomad4 ASJ AF: 0.554

Gnomad4 EAS AF: 0.465

Gnomad4 SAS AF: 0.481

Gnomad4 FIN AF: 0.587

Gnomad4 NFE AF: 0.619

Gnomad4 OTH AF: 0.513

Alfa AF: 0.548 Hom.: 2966

Bravo AF: 0.493

Asia WGS AF: 0.433 AC: 1509 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	11
DANN	Benign	0.80

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: rs8043227; hg19: chr15-78768871;