chr15-78474287-C-T

Variant names:

• chr15-78474287-C-T
• rs1504549
• ENST00000560440.5:c.*897C>T

Variant summary

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

The ENST00000560440.5(IREB2):​c.*897C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.506 in 151,972 control chromosomes in the GnomAD database, including 20,815 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 (20815 hom., cov: 32)
  • Exomes 𝑓: 0.25 (0 hom.)
• Consequence: IREB2 ENST00000560440.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.25
• Publications: 10 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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.613 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IREB2	NM_004136.4	c.1023+906C>T		intron_variant	Intron 8 of 21	ENST00000258886.13	NP_004127.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IREB2	ENST00000560440.5	c.*897C>T		3_prime_UTR_variant	Exon 8 of 8	1		ENSP00000452938.1
IREB2	ENST00000258886.13	c.1023+906C>T		intron_variant	Intron 8 of 21	1	NM_004136.4	ENSP00000258886.8
IREB2	ENST00000558570.5	n.*290+906C>T		intron_variant	Intron 7 of 20	1		ENSP00000454063.1

Frequencies

GnomAD3 genomes AF: 0.506 AC: 76801 AN: 151850 Hom.: 20803 Cov.: 32

Gnomad AFR AF: 0.304

Gnomad AMI AF: 0.685

Gnomad AMR AF: 0.498

Gnomad ASJ AF: 0.552

Gnomad EAS AF: 0.464

Gnomad SAS AF: 0.479

Gnomad FIN AF: 0.586

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.618

Gnomad OTH AF: 0.516

GnomAD4 exome AF: 0.250 AC: 1 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 1 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AF: 0.00 AC: 0 AN: 2

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.506 AC: 76835 AN: 151968 Hom.: 20815 Cov.: 32 AF XY: 0.505 AC XY: 37533 AN XY: 74278

African (AFR) AF: 0.304 AC: 12582 AN: 41410

American (AMR) AF: 0.497 AC: 7595 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.552 AC: 1910 AN: 3462

East Asian (EAS) AF: 0.465 AC: 2401 AN: 5168

South Asian (SAS) AF: 0.479 AC: 2307 AN: 4814

European-Finnish (FIN) AF: 0.586 AC: 6183 AN: 10546

Middle Eastern (MID) AF: 0.537 AC: 158 AN: 294

European-Non Finnish (NFE) AF: 0.618 AC: 41993 AN: 67980

Other (OTH) AF: 0.511 AC: 1081 AN: 2114

Alfa AF: 0.523 Hom.: 4505

Bravo AF: 0.492

Asia WGS AF: 0.432 AC: 1504 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.0060
DANN	Benign	0.45
PhyloP100		-3.2
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: rs1504549; hg19: chr15-78766629;