chr15-78500185-T-C

Variant names:

• chr15-78500185-T-C
• rs1062980
• NM_004136.4:c.*2042T>C

Variant summary

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

The NM_004136.4(IREB2):​c.*2042T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.398 in 151,970 control chromosomes in the GnomAD database, including 12,202 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 0.40 (12198 hom., cov: 31)
  • Exomes 𝑓: 0.47 (4 hom.)
• Consequence: IREB2 NM_004136.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.594
• Publications: 41 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=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.494 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.*2042T>C		3_prime_UTR	Exon 22 of 22	NP_004127.2
	IREB2	NM_001320942.2		c.*2042T>C		3_prime_UTR	Exon 22 of 22	NP_001307871.2
	IREB2	NM_001354994.2		c.*2042T>C		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.*2042T>C		3_prime_UTR	Exon 22 of 22	ENSP00000258886.8

Frequencies

GnomAD3 genomes AF: 0.398 AC: 60382 AN: 151818 Hom.: 12176 Cov.: 31

Gnomad AFR AF: 0.380

Gnomad AMI AF: 0.305

Gnomad AMR AF: 0.467

Gnomad ASJ AF: 0.415

Gnomad EAS AF: 0.423

Gnomad SAS AF: 0.511

Gnomad FIN AF: 0.414

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.380

Gnomad OTH AF: 0.415

GnomAD4 exome AF: 0.471 AC: 16 AN: 34 Hom.: 4 Cov.: 0 AF XY: 0.455 AC XY: 10 AN XY: 22

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.00 AC: 0 AN: 2

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) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.500 AC: 12 AN: 24

Other (OTH) AF: 0.750 AC: 3 AN: 4

GnomAD4 genome AF: 0.398 AC: 60434 AN: 151936 Hom.: 12198 Cov.: 31 AF XY: 0.401 AC XY: 29756 AN XY: 74250

African (AFR) AF: 0.380 AC: 15757 AN: 41438

American (AMR) AF: 0.467 AC: 7132 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.415 AC: 1441 AN: 3470

East Asian (EAS) AF: 0.423 AC: 2179 AN: 5156

South Asian (SAS) AF: 0.511 AC: 2464 AN: 4826

European-Finnish (FIN) AF: 0.414 AC: 4362 AN: 10532

Middle Eastern (MID) AF: 0.418 AC: 123 AN: 294

European-Non Finnish (NFE) AF: 0.380 AC: 25812 AN: 67950

Other (OTH) AF: 0.422 AC: 886 AN: 2102

Alfa AF: 0.393 Hom.: 13572

Bravo AF: 0.399

Asia WGS AF: 0.505 AC: 1752 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.1
DANN	Benign	0.61
PhyloP100		-0.59
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: rs1062980; hg19: chr15-78792527;