15-78441048-A-T

Variant names:

• chr15-78441048-A-T
• rs17483686
• NM_004136.4:c.106+1167A>T

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+1167A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.292 in 152,076 control chromosomes in the GnomAD database, including 6,848 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 0.29 (6848 hom., cov: 32)
• Consequence: IREB2 NM_004136.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.543
• Publications: 18 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.342 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.106+1167A>T		intron	N/A	NP_004127.2	P48200-1
	IREB2	NM_001320942.2		c.-66+1167A>T		intron	N/A	NP_001307871.2
	IREB2	NM_001354994.2		c.-66+1167A>T		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.106+1167A>T		intron	N/A	ENSP00000258886.8	P48200-1
	IREB2	ENST00000560440.5	TSL:1	c.106+1167A>T		intron	N/A	ENSP00000452938.1	P48200-2
	IREB2	ENST00000558570.5	TSL:1	n.106+1167A>T		intron	N/A	ENSP00000454063.1	H0YNL8

Frequencies

GnomAD3 genomes AF: 0.292 AC: 44356 AN: 151958 Hom.: 6839 Cov.: 32

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.362

Gnomad AMR AF: 0.280

Gnomad ASJ AF: 0.353

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.346

Gnomad OTH AF: 0.307

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

GnomAD4 genome AF: 0.292 AC: 44404 AN: 152076 Hom.: 6848 Cov.: 32 AF XY: 0.289 AC XY: 21498 AN XY: 74308

African (AFR) AF: 0.220 AC: 9143 AN: 41508

American (AMR) AF: 0.280 AC: 4280 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.353 AC: 1224 AN: 3466

East Asian (EAS) AF: 0.137 AC: 709 AN: 5178

South Asian (SAS) AF: 0.234 AC: 1126 AN: 4820

European-Finnish (FIN) AF: 0.317 AC: 3342 AN: 10544

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.346 AC: 23490 AN: 67974

Other (OTH) AF: 0.305 AC: 643 AN: 2110

Alfa AF: 0.309 Hom.: 941

Bravo AF: 0.286

Asia WGS AF: 0.201 AC: 700 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	8.4
DANN	Benign	0.71
PhyloP100		0.54
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: rs17483686; hg19: chr15-78733390; COSMIC: COSV107261941;