rs8043227

Variant names:

• chr15-78476529-C-G
• rs8043227
• ENST00000560440.5:c.*3139C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000560440.5(IREB2):​c.*3139C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.547 in 470,970 control chromosomes in the GnomAD database, including 73,775 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 0.51 (20888 hom., cov: 32)
  • Exomes 𝑓: 0.57 (52887 hom.)
• Consequence: IREB2 ENST00000560440.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0790
• Publications: 19 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=-0.73).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.614 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IREB2	NM_004136.4	c.1195+170C>G		intron_variant	Intron 9 of 21	ENST00000258886.13	NP_004127.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IREB2	ENST00000560440.5	c.*3139C>G		3_prime_UTR_variant	Exon 8 of 8	1		ENSP00000452938.1
IREB2	ENST00000258886.13	c.1195+170C>G		intron_variant	Intron 9 of 21	1	NM_004136.4	ENSP00000258886.8
IREB2	ENST00000558570.5	n.*462+170C>G		intron_variant	Intron 8 of 20	1		ENSP00000454063.1

Frequencies

GnomAD3 genomes AF: 0.506 AC: 76962 AN: 151950 Hom.: 20876 Cov.: 32

Gnomad AFR AF: 0.305

Gnomad AMI AF: 0.687

Gnomad AMR AF: 0.498

Gnomad ASJ AF: 0.554

Gnomad EAS AF: 0.464

Gnomad SAS AF: 0.480

Gnomad FIN AF: 0.587

Gnomad MID AF: 0.548

Gnomad NFE AF: 0.619

Gnomad OTH AF: 0.518

GnomAD4 exome AF: 0.567 AC: 180771 AN: 318902 Hom.: 52887 Cov.: 5 AF XY: 0.565 AC XY: 93265 AN XY: 164972

African (AFR) AF: 0.291 AC: 2994 AN: 10280

American (AMR) AF: 0.490 AC: 6630 AN: 13542

Ashkenazi Jewish (ASJ) AF: 0.526 AC: 5333 AN: 10138

East Asian (EAS) AF: 0.429 AC: 11415 AN: 26626

South Asian (SAS) AF: 0.460 AC: 8005 AN: 17384

European-Finnish (FIN) AF: 0.587 AC: 12392 AN: 21112

Middle Eastern (MID) AF: 0.550 AC: 785 AN: 1426

European-Non Finnish (NFE) AF: 0.617 AC: 123069 AN: 199612

Other (OTH) AF: 0.540 AC: 10148 AN: 18782

GnomAD4 genome AF: 0.506 AC: 76996 AN: 152068 Hom.: 20888 Cov.: 32 AF XY: 0.506 AC XY: 37621 AN XY: 74320

African (AFR) AF: 0.305 AC: 12637 AN: 41474

American (AMR) AF: 0.497 AC: 7600 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.554 AC: 1922 AN: 3470

East Asian (EAS) AF: 0.465 AC: 2410 AN: 5180

South Asian (SAS) AF: 0.481 AC: 2321 AN: 4826

European-Finnish (FIN) AF: 0.587 AC: 6195 AN: 10558

Middle Eastern (MID) AF: 0.548 AC: 160 AN: 292

European-Non Finnish (NFE) AF: 0.619 AC: 42044 AN: 67964

Other (OTH) AF: 0.513 AC: 1082 AN: 2110

Alfa AF: 0.548 Hom.: 2966

Bravo AF: 0.493

Asia WGS AF: 0.433 AC: 1509 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	11
DANN	Benign	0.80
PhyloP100		0.079
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: rs8043227; hg19: chr15-78768871;