rs11858836

Variant names:

• chr15-78490935-G-A
• rs11858836
• NM_004136.4:c.2324+174G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-78490935-G-A
• chr15-78490935-G-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.2324+174G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 151,578 control chromosomes in the GnomAD database, including 5,401 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 0.24 (5401 hom., cov: 30)
• Consequence: IREB2 NM_004136.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.535
• Publications: 31 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=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.336 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IREB2	NM_004136.4	c.2324+174G>A		intron_variant	Intron 18 of 21	ENST00000258886.13	NP_004127.2
IREB2	NM_001320942.2	c.2153+174G>A		intron_variant	Intron 18 of 21		NP_001307871.2
IREB2	NM_001354994.2	c.2153+174G>A		intron_variant	Intron 18 of 21		NP_001341923.2
IREB2	NM_001320941.2	c.1574+174G>A		intron_variant	Intron 17 of 20		NP_001307870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IREB2	ENST00000258886.13	c.2324+174G>A		intron_variant	Intron 18 of 21	1	NM_004136.4	ENSP00000258886.8
IREB2	ENST00000558570.5	n.*1591+174G>A		intron_variant	Intron 17 of 20	1		ENSP00000454063.1

Frequencies

GnomAD3 genomes AF: 0.236 AC: 35703 AN: 151460 Hom.: 5396 Cov.: 30

Gnomad AFR AF: 0.0645

Gnomad AMI AF: 0.361

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.344

Gnomad EAS AF: 0.0395

Gnomad SAS AF: 0.202

Gnomad FIN AF: 0.315

Gnomad MID AF: 0.366

Gnomad NFE AF: 0.340

Gnomad OTH AF: 0.259

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

GnomAD4 genome AF: 0.236 AC: 35727 AN: 151578 Hom.: 5401 Cov.: 30 AF XY: 0.233 AC XY: 17269 AN XY: 74012

African (AFR) AF: 0.0647 AC: 2677 AN: 41352

American (AMR) AF: 0.221 AC: 3363 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.344 AC: 1194 AN: 3466

East Asian (EAS) AF: 0.0398 AC: 205 AN: 5154

South Asian (SAS) AF: 0.204 AC: 977 AN: 4794

European-Finnish (FIN) AF: 0.315 AC: 3289 AN: 10450

Middle Eastern (MID) AF: 0.370 AC: 108 AN: 292

European-Non Finnish (NFE) AF: 0.340 AC: 23046 AN: 67864

Other (OTH) AF: 0.258 AC: 541 AN: 2100

Alfa AF: 0.285 Hom.: 15544

Bravo AF: 0.221

Asia WGS AF: 0.124 AC: 433 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.37
DANN	Benign	0.65
PhyloP100		-0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	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: rs11858836; hg19: chr15-78783277; COSMIC: COSV51922372; COSMIC: COSV51922372;