chr15-78480334-A-G

Variant names:

• chr15-78480334-A-G
• rs17484524
• NM_004136.4:c.1296+1937A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004136.4(IREB2):​c.1296+1937A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 152,176 control chromosomes in the GnomAD database, including 5,434 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 0.23 (5434 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: IREB2 NM_004136.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.92
• Publications: 19 publications found

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]

IREB2 Gene-Disease associations (from GenCC):

• neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P

ENSG00000259474 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.337 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004136.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IREB2	NM_004136.4	MANE Select	c.1296+1937A>G		intron	N/A	NP_004127.2	P48200-1
	IREB2	NM_001320942.2		c.1125+1937A>G		intron	N/A	NP_001307871.2
	IREB2	NM_001354994.2		c.1125+1937A>G		intron	N/A	NP_001341923.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IREB2	ENST00000258886.13	TSL:1 MANE Select	c.1296+1937A>G		intron	N/A	ENSP00000258886.8	P48200-1
	IREB2	ENST00000558570.5	TSL:1	n.*563+1937A>G		intron	N/A	ENSP00000454063.1	H0YNL8
	IREB2	ENST00000925635.1		c.1326+1937A>G		intron	N/A	ENSP00000595694.1

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35564 AN: 152058 Hom.: 5432 Cov.: 32

Gnomad AFR AF: 0.0562

Gnomad AMI AF: 0.363

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.352

Gnomad EAS AF: 0.0398

Gnomad SAS AF: 0.203

Gnomad FIN AF: 0.313

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.257

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 4 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.234 AC: 35570 AN: 152176 Hom.: 5434 Cov.: 32 AF XY: 0.231 AC XY: 17173 AN XY: 74382

African (AFR) AF: 0.0561 AC: 2329 AN: 41546

American (AMR) AF: 0.222 AC: 3389 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.352 AC: 1221 AN: 3472

East Asian (EAS) AF: 0.0401 AC: 208 AN: 5188

South Asian (SAS) AF: 0.205 AC: 988 AN: 4822

European-Finnish (FIN) AF: 0.313 AC: 3308 AN: 10566

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.341 AC: 23152 AN: 67982

Other (OTH) AF: 0.255 AC: 538 AN: 2110

Alfa AF: 0.308 Hom.: 3299

Bravo AF: 0.218

Asia WGS AF: 0.123 AC: 430 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.0
DANN	Benign	0.40
PhyloP100		1.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17484524; hg19: chr15-78772676;