chr15-78461760-A-G

Variant names:

• chr15-78461760-A-G
• rs2009746
• NM_004136.4:c.107-1162A>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.107-1162A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 152,096 control chromosomes in the GnomAD database, including 6,717 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 (6717 hom., cov: 32)
• Consequence: IREB2 NM_004136.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00100
• Publications: 25 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=-0.93).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.343 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IREB2	NM_004136.4	MANE Select	c.107-1162A>G		intron	N/A	NP_004127.2
	IREB2	NM_001320942.2		c.-65-1162A>G		intron	N/A	NP_001307871.2
	IREB2	NM_001354994.2		c.-65-1162A>G		intron	N/A	NP_001341923.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IREB2	ENST00000258886.13	TSL:1 MANE Select	c.107-1162A>G		intron	N/A	ENSP00000258886.8
	IREB2	ENST00000560440.5	TSL:1	c.107-1162A>G		intron	N/A	ENSP00000452938.1
	IREB2	ENST00000558570.5	TSL:1	n.107-1162A>G		intron	N/A	ENSP00000454063.1

Frequencies

GnomAD3 genomes AF: 0.287 AC: 43681 AN: 151978 Hom.: 6714 Cov.: 32

Gnomad AFR AF: 0.200

Gnomad AMI AF: 0.362

Gnomad AMR AF: 0.279

Gnomad ASJ AF: 0.365

Gnomad EAS AF: 0.140

Gnomad SAS AF: 0.231

Gnomad FIN AF: 0.318

Gnomad MID AF: 0.398

Gnomad NFE AF: 0.347

Gnomad OTH AF: 0.302

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

GnomAD4 genome AF: 0.287 AC: 43712 AN: 152096 Hom.: 6717 Cov.: 32 AF XY: 0.285 AC XY: 21162 AN XY: 74320

African (AFR) AF: 0.200 AC: 8318 AN: 41528

American (AMR) AF: 0.279 AC: 4263 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.365 AC: 1266 AN: 3470

East Asian (EAS) AF: 0.141 AC: 727 AN: 5168

South Asian (SAS) AF: 0.233 AC: 1123 AN: 4820

European-Finnish (FIN) AF: 0.318 AC: 3353 AN: 10544

Middle Eastern (MID) AF: 0.397 AC: 116 AN: 292

European-Non Finnish (NFE) AF: 0.347 AC: 23581 AN: 67968

Other (OTH) AF: 0.301 AC: 635 AN: 2112

Alfa AF: 0.326 Hom.: 4849

Bravo AF: 0.281

Asia WGS AF: 0.200 AC: 699 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	2.8
DANN	Benign	0.51
PhyloP100		0.0010
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: rs2009746; hg19: chr15-78754102;