rs7181486

Positions:

• chr15-78449276-T-C

Variant summary

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

The NM_004136.4(IREB2):​c.106+9395T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.293 in 152,124 control chromosomes in the GnomAD database, including 6,859 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 0.29 (6859 hom., cov: 32)
• Consequence: IREB2 NM_004136.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.262

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=-0.88).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.342 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IREB2	NM_004136.4	c.106+9395T>C		intron_variant		ENST00000258886.13	NP_004127.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IREB2	ENST00000258886.13	c.106+9395T>C		intron_variant		1	NM_004136.4	ENSP00000258886	P1

Frequencies

GnomAD3 genomes AF: 0.292 AC: 44454 AN: 152004 Hom.: 6850 Cov.: 32

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.362

Gnomad AMR AF: 0.280

Gnomad ASJ AF: 0.353

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.346

Gnomad OTH AF: 0.308

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

GnomAD4 genome AF: 0.293 AC: 44503 AN: 152124 Hom.: 6859 Cov.: 32 AF XY: 0.290 AC XY: 21553 AN XY: 74348

Gnomad4 AFR AF: 0.221

Gnomad4 AMR AF: 0.280

Gnomad4 ASJ AF: 0.353

Gnomad4 EAS AF: 0.137

Gnomad4 SAS AF: 0.234

Gnomad4 FIN AF: 0.317

Gnomad4 NFE AF: 0.346

Gnomad4 OTH AF: 0.306

Alfa AF: 0.304 Hom.: 2049

Bravo AF: 0.287

Asia WGS AF: 0.201 AC: 700 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.4
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: rs7181486; hg19: chr15-78741618; COSMIC: COSV51925095;