15-78500355-A-G

Position:

• chr15-78500355-A-G

Variant summary

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

The NM_004136.4(IREB2):​c.*2212A>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 0.0447 in 152,256 control chromosomes in the GnomAD database, including 218 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 0.045 (218 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: IREB2 NM_004136.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.25

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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.071 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IREB2	NM_004136.4	c.*2212A>G		3_prime_UTR_variant	22/22	ENST00000258886.13	NP_004127.2
IREB2	NM_001320942.2	c.*2212A>G		3_prime_UTR_variant	22/22		NP_001307871.2
IREB2	NM_001354994.2	c.*2212A>G		3_prime_UTR_variant	22/22		NP_001341923.2
IREB2	NM_001320941.2	c.*2212A>G		3_prime_UTR_variant	21/21		NP_001307870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IREB2	ENST00000258886.13	c.*2212A>G		3_prime_UTR_variant	22/22	1	NM_004136.4	ENSP00000258886.8

Frequencies

GnomAD3 genomes AF: 0.0448 AC: 6812 AN: 152138 Hom.: 218 Cov.: 31

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.0244

Gnomad ASJ AF: 0.0421

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0161

Gnomad FIN AF: 0.0505

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0727

Gnomad OTH AF: 0.0334

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

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.0447 AC: 6811 AN: 152256 Hom.: 218 Cov.: 31 AF XY: 0.0432 AC XY: 3213 AN XY: 74446

Gnomad4 AFR AF: 0.0136

Gnomad4 AMR AF: 0.0243

Gnomad4 ASJ AF: 0.0421

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0161

Gnomad4 FIN AF: 0.0505

Gnomad4 NFE AF: 0.0727

Gnomad4 OTH AF: 0.0331

Alfa AF: 0.0634 Hom.: 153

Bravo AF: 0.0398

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.050
DANN	Benign	0.65
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: rs17406522; hg19: chr15-78792697;