NM_004136.4:c.2596-245G>A

Variant names:

• chr15-78496881-G-A
• rs965604
• NM_004136.4:c.2596-245G>A

Variant summary

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

The NM_004136.4(IREB2):​c.2596-245G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.505 in 151,986 control chromosomes in the GnomAD database, including 20,811 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 (20811 hom., cov: 32)
• Consequence: IREB2 NM_004136.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.33
• Publications: 25 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=-0.83).
• 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.2596-245G>A		intron_variant	Intron 20 of 21	ENST00000258886.13	NP_004127.2
IREB2	NM_001320942.2	c.2425-245G>A		intron_variant	Intron 20 of 21		NP_001307871.2
IREB2	NM_001354994.2	c.2425-245G>A		intron_variant	Intron 20 of 21		NP_001341923.2
IREB2	NM_001320941.2	c.1846-245G>A		intron_variant	Intron 19 of 20		NP_001307870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IREB2	ENST00000258886.13	c.2596-245G>A		intron_variant	Intron 20 of 21	1	NM_004136.4	ENSP00000258886.8
IREB2	ENST00000558570.5	n.*1863-245G>A		intron_variant	Intron 19 of 20	1		ENSP00000454063.1
IREB2	ENST00000559091.1	c.55-245G>A		intron_variant	Intron 1 of 1	3		ENSP00000453863.1

Frequencies

GnomAD3 genomes AF: 0.506 AC: 76773 AN: 151868 Hom.: 20799 Cov.: 32

Gnomad AFR AF: 0.303

Gnomad AMI AF: 0.685

Gnomad AMR AF: 0.496

Gnomad ASJ AF: 0.551

Gnomad EAS AF: 0.464

Gnomad SAS AF: 0.479

Gnomad FIN AF: 0.586

Gnomad MID AF: 0.544

Gnomad NFE AF: 0.618

Gnomad OTH AF: 0.516

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.505 AC: 76807 AN: 151986 Hom.: 20811 Cov.: 32 AF XY: 0.505 AC XY: 37510 AN XY: 74282

African (AFR) AF: 0.303 AC: 12575 AN: 41434

American (AMR) AF: 0.495 AC: 7561 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.551 AC: 1912 AN: 3470

East Asian (EAS) AF: 0.465 AC: 2401 AN: 5166

South Asian (SAS) AF: 0.479 AC: 2310 AN: 4818

European-Finnish (FIN) AF: 0.586 AC: 6180 AN: 10552

Middle Eastern (MID) AF: 0.544 AC: 160 AN: 294

European-Non Finnish (NFE) AF: 0.618 AC: 42003 AN: 67966

Other (OTH) AF: 0.511 AC: 1080 AN: 2112

Alfa AF: 0.576 Hom.: 31411

Bravo AF: 0.492

Asia WGS AF: 0.434 AC: 1510 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.4
DANN	Benign	0.65
PhyloP100		1.3
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: rs965604; hg19: chr15-78789223;