rs2568483

Variant names:

• chr15-78460001-G-A
• rs2568483
• NM_004136.4:c.107-2921G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-78460001-G-A
• chr15-78460001-G-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.107-2921G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.767 in 152,214 control chromosomes in the GnomAD database, including 44,994 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 0.77 (44994 hom., cov: 33)
• Consequence: IREB2 NM_004136.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.858
• Publications: 16 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.799 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IREB2	NM_004136.4	c.107-2921G>A		intron_variant	Intron 2 of 21	ENST00000258886.13	NP_004127.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IREB2	ENST00000258886.13	c.107-2921G>A		intron_variant	Intron 2 of 21	1	NM_004136.4	ENSP00000258886.8

Frequencies

GnomAD3 genomes AF: 0.767 AC: 116647 AN: 152096 Hom.: 44945 Cov.: 33

Gnomad AFR AF: 0.806

Gnomad AMI AF: 0.854

Gnomad AMR AF: 0.651

Gnomad ASJ AF: 0.790

Gnomad EAS AF: 0.729

Gnomad SAS AF: 0.649

Gnomad FIN AF: 0.750

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.781

Gnomad OTH AF: 0.757

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

GnomAD4 genome AF: 0.767 AC: 116748 AN: 152214 Hom.: 44994 Cov.: 33 AF XY: 0.763 AC XY: 56793 AN XY: 74422

African (AFR) AF: 0.806 AC: 33471 AN: 41522

American (AMR) AF: 0.651 AC: 9946 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.790 AC: 2744 AN: 3472

East Asian (EAS) AF: 0.729 AC: 3777 AN: 5178

South Asian (SAS) AF: 0.649 AC: 3131 AN: 4822

European-Finnish (FIN) AF: 0.750 AC: 7952 AN: 10604

Middle Eastern (MID) AF: 0.701 AC: 206 AN: 294

European-Non Finnish (NFE) AF: 0.781 AC: 53150 AN: 68016

Other (OTH) AF: 0.756 AC: 1594 AN: 2108

Alfa AF: 0.722 Hom.: 5636

Bravo AF: 0.764

Asia WGS AF: 0.665 AC: 2312 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.8
DANN	Benign	0.64
PhyloP100		-0.86
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: rs2568483; hg19: chr15-78752343;