15-78443013-C-G

Variant names:

• chr15-78443013-C-G
• rs8041628
• NM_004136.4:c.106+3132C>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.106+3132C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.365 in 152,082 control chromosomes in the GnomAD database, including 10,864 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 0.37 (10864 hom., cov: 32)
• Consequence: IREB2 NM_004136.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0290
• Publications: 5 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: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.46 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IREB2	NM_004136.4	c.106+3132C>G		intron_variant	Intron 2 of 21	ENST00000258886.13	NP_004127.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IREB2	ENST00000258886.13	c.106+3132C>G		intron_variant	Intron 2 of 21	1	NM_004136.4	ENSP00000258886.8

Frequencies

GnomAD3 genomes AF: 0.365 AC: 55526 AN: 151964 Hom.: 10862 Cov.: 32

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.490

Gnomad AMR AF: 0.328

Gnomad ASJ AF: 0.403

Gnomad EAS AF: 0.476

Gnomad SAS AF: 0.407

Gnomad FIN AF: 0.433

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.434

Gnomad OTH AF: 0.371

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

GnomAD4 genome AF: 0.365 AC: 55548 AN: 152082 Hom.: 10864 Cov.: 32 AF XY: 0.367 AC XY: 27303 AN XY: 74326

African (AFR) AF: 0.226 AC: 9368 AN: 41516

American (AMR) AF: 0.327 AC: 5001 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.403 AC: 1399 AN: 3468

East Asian (EAS) AF: 0.476 AC: 2457 AN: 5160

South Asian (SAS) AF: 0.406 AC: 1959 AN: 4824

European-Finnish (FIN) AF: 0.433 AC: 4568 AN: 10560

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.434 AC: 29485 AN: 67956

Other (OTH) AF: 0.373 AC: 787 AN: 2108

Alfa AF: 0.275 Hom.: 728

Bravo AF: 0.354

Asia WGS AF: 0.400 AC: 1390 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.8
DANN	Benign	0.33
PhyloP100		0.029
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: rs8041628; hg19: chr15-78735355;