15-78438249-C-T

Variant names:

• chr15-78438249-C-T
• rs954144
• NM_004136.4:c.-89C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4 BA1

The NM_004136.4(IREB2):​c.-89C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.41 in 1,007,746 control chromosomes in the GnomAD database, including 87,252 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 0.36 (10857 hom., cov: 32)
  • Exomes 𝑓: 0.42 (76395 hom.)
• Consequence: IREB2 NM_004136.4 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.210
• Publications: 21 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.16).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.471 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IREB2	NM_004136.4	c.-89C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 22	ENST00000258886.13	NP_004127.2
IREB2	NM_004136.4	c.-89C>T		5_prime_UTR_variant	Exon 1 of 22	ENST00000258886.13	NP_004127.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IREB2	ENST00000258886.13	c.-89C>T		5_prime_UTR_premature_start_codon_gain_variant	Exon 1 of 22	1	NM_004136.4	ENSP00000258886.8
IREB2	ENST00000258886.13	c.-89C>T		5_prime_UTR_variant	Exon 1 of 22	1	NM_004136.4	ENSP00000258886.8

Frequencies

GnomAD3 genomes AF: 0.365 AC: 55473 AN: 151936 Hom.: 10855 Cov.: 32

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.480

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.406

Gnomad EAS AF: 0.487

Gnomad SAS AF: 0.398

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.434

Gnomad OTH AF: 0.370

GnomAD4 exome AF: 0.418 AC: 357749 AN: 855692 Hom.: 76395 Cov.: 11 AF XY: 0.418 AC XY: 184154 AN XY: 440590

African (AFR) AF: 0.219 AC: 4675 AN: 21332

American (AMR) AF: 0.317 AC: 10995 AN: 34690

Ashkenazi Jewish (ASJ) AF: 0.397 AC: 8611 AN: 21688

East Asian (EAS) AF: 0.418 AC: 13937 AN: 33336

South Asian (SAS) AF: 0.381 AC: 26079 AN: 68438

European-Finnish (FIN) AF: 0.425 AC: 20831 AN: 48974

Middle Eastern (MID) AF: 0.318 AC: 1485 AN: 4664

European-Non Finnish (NFE) AF: 0.438 AC: 254867 AN: 582460

Other (OTH) AF: 0.406 AC: 16269 AN: 40110

GnomAD4 genome AF: 0.365 AC: 55494 AN: 152054 Hom.: 10857 Cov.: 32 AF XY: 0.367 AC XY: 27294 AN XY: 74336

African (AFR) AF: 0.226 AC: 9359 AN: 41494

American (AMR) AF: 0.326 AC: 4986 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.406 AC: 1409 AN: 3468

East Asian (EAS) AF: 0.487 AC: 2502 AN: 5136

South Asian (SAS) AF: 0.396 AC: 1910 AN: 4818

European-Finnish (FIN) AF: 0.432 AC: 4571 AN: 10584

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.433 AC: 29458 AN: 67954

Other (OTH) AF: 0.373 AC: 788 AN: 2114

Alfa AF: 0.349 Hom.: 2305

Bravo AF: 0.354

Asia WGS AF: 0.399 AC: 1386 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.16
CADD	Benign	15
DANN	Benign	0.89
PhyloP100		-0.21
PromoterAI		-0.049	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	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: rs954144; hg19: chr15-78730591; COSMIC: COSV51921459; COSMIC: COSV51921459;