chr15-78498719-C-T

Variant names:

• chr15-78498719-C-T
• rs3743079
• NM_004136.4:c.*576C>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.*576C>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 0.151 in 152,480 control chromosomes in the GnomAD database, including 1,784 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 0.15 (1779 hom., cov: 33)
  • Exomes 𝑓: 0.14 (5 hom.)
• Consequence: IREB2 NM_004136.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.612
• Publications: 20 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=-0.75).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.158 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.*576C>T		3_prime_UTR	Exon 22 of 22	NP_004127.2
	IREB2	NM_001320942.2		c.*576C>T		3_prime_UTR	Exon 22 of 22	NP_001307871.2
	IREB2	NM_001354994.2		c.*576C>T		3_prime_UTR	Exon 22 of 22	NP_001341923.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IREB2	ENST00000258886.13	TSL:1 MANE Select	c.*576C>T		3_prime_UTR	Exon 22 of 22	ENSP00000258886.8

Frequencies

GnomAD3 genomes AF: 0.151 AC: 23003 AN: 152060 Hom.: 1772 Cov.: 33

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.204

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.164

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.159

GnomAD4 exome AF: 0.136 AC: 41 AN: 302 Hom.: 5 Cov.: 0 AF XY: 0.149 AC XY: 29 AN XY: 194

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.00 AC: 0 AN: 4

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.108 AC: 24 AN: 222

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.229 AC: 16 AN: 70

Other (OTH) AF: 0.250 AC: 1 AN: 4

GnomAD4 genome AF: 0.151 AC: 23039 AN: 152178 Hom.: 1779 Cov.: 33 AF XY: 0.151 AC XY: 11251 AN XY: 74404

African (AFR) AF: 0.142 AC: 5909 AN: 41520

American (AMR) AF: 0.110 AC: 1686 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 710 AN: 3472

East Asian (EAS) AF: 0.148 AC: 766 AN: 5178

South Asian (SAS) AF: 0.161 AC: 774 AN: 4822

European-Finnish (FIN) AF: 0.164 AC: 1731 AN: 10578

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.161 AC: 10937 AN: 68004

Other (OTH) AF: 0.165 AC: 348 AN: 2110

Alfa AF: 0.159 Hom.: 7660

Bravo AF: 0.148

Asia WGS AF: 0.167 AC: 580 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	6.8
DANN	Benign	0.69
PhyloP100		0.61
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: rs3743079; hg19: chr15-78791061;