15-78438249-C-T

Position:

• chr15-78438249-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4 BA1

The NM_004136.4(IREB2):​c.-89C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.41 in 1,007,746 control chromosomes in the GnomAD database, including 87,252 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 0.36 (10857 hom., cov: 32)
  • Exomes 𝑓: 0.42 (76395 hom.)
• Consequence: IREB2 NM_004136.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.210

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.16).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.471 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IREB2	NM_004136.4	c.-89C>T		5_prime_UTR_variant	1/22	ENST00000258886.13
IREB2	NM_001320941.2	c.-769C>T		5_prime_UTR_variant	1/21
IREB2	NM_001320943.2	c.-89C>T		5_prime_UTR_variant	1/8
IREB2	NM_001354994.2	c.-153+528C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IREB2	ENST00000258886.13	c.-89C>T		5_prime_UTR_variant	1/22	1	NM_004136.4	P1

Frequencies

GnomAD3 genomes AF: 0.365 AC: 55473 AN: 151936 Hom.: 10855 Cov.: 32

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.480

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.406

Gnomad EAS AF: 0.487

Gnomad SAS AF: 0.398

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.434

Gnomad OTH AF: 0.370

GnomAD4 exome AF: 0.418 AC: 357749 AN: 855692 Hom.: 76395 Cov.: 11 AF XY: 0.418 AC XY: 184154 AN XY: 440590

Gnomad4 AFR exome AF: 0.219

Gnomad4 AMR exome AF: 0.317

Gnomad4 ASJ exome AF: 0.397

Gnomad4 EAS exome AF: 0.418

Gnomad4 SAS exome AF: 0.381

Gnomad4 FIN exome AF: 0.425

Gnomad4 NFE exome AF: 0.438

Gnomad4 OTH exome AF: 0.406

GnomAD4 genome AF: 0.365 AC: 55494 AN: 152054 Hom.: 10857 Cov.: 32 AF XY: 0.367 AC XY: 27294 AN XY: 74336

Gnomad4 AFR AF: 0.226

Gnomad4 AMR AF: 0.326

Gnomad4 ASJ AF: 0.406

Gnomad4 EAS AF: 0.487

Gnomad4 SAS AF: 0.396

Gnomad4 FIN AF: 0.432

Gnomad4 NFE AF: 0.433

Gnomad4 OTH AF: 0.373

Alfa AF: 0.256 Hom.: 651

Bravo AF: 0.354

Asia WGS AF: 0.399 AC: 1386 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.16
CADD	Benign	15
DANN	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs954144; hg19: chr15-78730591; COSMIC: COSV51921459; COSMIC: COSV51921459;