chr15-78441389-T-C

Variant names:

• chr15-78441389-T-C
• rs17483721
• NM_004136.4:c.106+1508T>C

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+1508T>C 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 152,156 control chromosomes in the GnomAD database, including 6,846 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 (6846 hom., cov: 33)
• Consequence: IREB2 NM_004136.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.50
• Publications: 32 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=-0.81).
• 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+1508T>C		intron	N/A	NP_004127.2	P48200-1
	IREB2	NM_001320942.2		c.-66+1508T>C		intron	N/A	NP_001307871.2
	IREB2	NM_001354994.2		c.-66+1508T>C		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+1508T>C		intron	N/A	ENSP00000258886.8	P48200-1
	IREB2	ENST00000560440.5	TSL:1	c.106+1508T>C		intron	N/A	ENSP00000452938.1	P48200-2
	IREB2	ENST00000558570.5	TSL:1	n.106+1508T>C		intron	N/A	ENSP00000454063.1	H0YNL8

Frequencies

GnomAD3 genomes AF: 0.292 AC: 44390 AN: 152038 Hom.: 6837 Cov.: 33

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.363

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: 0.395

Gnomad NFE AF: 0.346

Gnomad OTH AF: 0.304

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

GnomAD4 genome AF: 0.292 AC: 44438 AN: 152156 Hom.: 6846 Cov.: 33 AF XY: 0.289 AC XY: 21517 AN XY: 74392

African (AFR) AF: 0.221 AC: 9155 AN: 41518

American (AMR) AF: 0.280 AC: 4288 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.353 AC: 1225 AN: 3470

East Asian (EAS) AF: 0.137 AC: 710 AN: 5188

South Asian (SAS) AF: 0.234 AC: 1130 AN: 4828

European-Finnish (FIN) AF: 0.317 AC: 3356 AN: 10590

Middle Eastern (MID) AF: 0.394 AC: 115 AN: 292

European-Non Finnish (NFE) AF: 0.346 AC: 23491 AN: 67960

Other (OTH) AF: 0.303 AC: 638 AN: 2108

Alfa AF: 0.328 Hom.: 13686

Bravo AF: 0.286

Asia WGS AF: 0.201 AC: 699 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	20
DANN	Benign	0.86
PhyloP100		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs17483721; hg19: chr15-78733731;