chr15-78439466-T-A

Variant names:

• chr15-78439466-T-A
• rs924840
• NM_004136.4:c.20-329T>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.20-329T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.78 in 152,128 control chromosomes in the GnomAD database, including 46,534 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 0.78 (46534 hom., cov: 32)
• Consequence: IREB2 NM_004136.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.59
• Publications: 11 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.843 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IREB2	NM_004136.4	MANE Select	c.20-329T>A		intron	N/A	NP_004127.2
	IREB2	NM_001320942.2		c.-152-329T>A		intron	N/A	NP_001307871.2
	IREB2	NM_001354994.2		c.-152-329T>A		intron	N/A	NP_001341923.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IREB2	ENST00000258886.13	TSL:1 MANE Select	c.20-329T>A		intron	N/A	ENSP00000258886.8
	IREB2	ENST00000560440.5	TSL:1	c.20-329T>A		intron	N/A	ENSP00000452938.1
	IREB2	ENST00000558570.5	TSL:1	n.20-329T>A		intron	N/A	ENSP00000454063.1

Frequencies

GnomAD3 genomes AF: 0.779 AC: 118481 AN: 152010 Hom.: 46479 Cov.: 32

Gnomad AFR AF: 0.850

Gnomad AMI AF: 0.851

Gnomad AMR AF: 0.655

Gnomad ASJ AF: 0.794

Gnomad EAS AF: 0.729

Gnomad SAS AF: 0.649

Gnomad FIN AF: 0.749

Gnomad MID AF: 0.696

Gnomad NFE AF: 0.782

Gnomad OTH AF: 0.764

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

GnomAD4 genome AF: 0.780 AC: 118590 AN: 152128 Hom.: 46534 Cov.: 32 AF XY: 0.775 AC XY: 57623 AN XY: 74368

African (AFR) AF: 0.850 AC: 35294 AN: 41516

American (AMR) AF: 0.654 AC: 10003 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.794 AC: 2751 AN: 3466

East Asian (EAS) AF: 0.730 AC: 3781 AN: 5182

South Asian (SAS) AF: 0.650 AC: 3123 AN: 4806

European-Finnish (FIN) AF: 0.749 AC: 7901 AN: 10554

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

European-Non Finnish (NFE) AF: 0.782 AC: 53145 AN: 67998

Other (OTH) AF: 0.763 AC: 1613 AN: 2114

Alfa AF: 0.777 Hom.: 5730

Bravo AF: 0.779

Asia WGS AF: 0.666 AC: 2317 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.39
DANN	Benign	0.26
PhyloP100		-1.6
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: rs924840; hg19: chr15-78731808;