rs1062980

Positions:

• chr15-78500185-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.*2042T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.398 in 151,970 control chromosomes in the GnomAD database, including 12,202 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 0.40 (12198 hom., cov: 31)
  • Exomes 𝑓: 0.47 (4 hom.)
• Consequence: IREB2 NM_004136.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.594

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=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.494 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IREB2	NM_004136.4	c.*2042T>C		3_prime_UTR_variant	22/22	ENST00000258886.13	NP_004127.2
IREB2	NM_001320941.2	c.*2042T>C		3_prime_UTR_variant	21/21		NP_001307870.2
IREB2	NM_001320942.2	c.*2042T>C		3_prime_UTR_variant	22/22		NP_001307871.2
IREB2	NM_001354994.2	c.*2042T>C		3_prime_UTR_variant	22/22		NP_001341923.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IREB2	ENST00000258886.13	c.*2042T>C		3_prime_UTR_variant	22/22	1	NM_004136.4	ENSP00000258886	P1

Frequencies

GnomAD3 genomes AF: 0.398 AC: 60382 AN: 151818 Hom.: 12176 Cov.: 31

Gnomad AFR AF: 0.380

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.467

Gnomad ASJ AF: 0.415

Gnomad EAS AF: 0.423

Gnomad SAS AF: 0.511

Gnomad FIN AF: 0.414

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.380

Gnomad OTH AF: 0.415

GnomAD4 exome AF: 0.471 AC: 16 AN: 34 Hom.: 4 Cov.: 0 AF XY: 0.455 AC XY: 10 AN XY: 22

Gnomad4 AMR exome AF: 0.00

Gnomad4 FIN exome AF: 0.500

Gnomad4 NFE exome AF: 0.500

Gnomad4 OTH exome AF: 0.750

GnomAD4 genome AF: 0.398 AC: 60434 AN: 151936 Hom.: 12198 Cov.: 31 AF XY: 0.401 AC XY: 29756 AN XY: 74250

Gnomad4 AFR AF: 0.380

Gnomad4 AMR AF: 0.467

Gnomad4 ASJ AF: 0.415

Gnomad4 EAS AF: 0.423

Gnomad4 SAS AF: 0.511

Gnomad4 FIN AF: 0.414

Gnomad4 NFE AF: 0.380

Gnomad4 OTH AF: 0.422

Alfa AF: 0.393 Hom.: 11367

Bravo AF: 0.399

Asia WGS AF: 0.505 AC: 1752 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.1
DANN	Benign	0.61

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: rs1062980; hg19: chr15-78792527;