rs9920411

Variant names:

• chr15-78497759-G-A
• rs9920411
• NM_004136.4:c.2782-274G>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.2782-274G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.936 in 152,246 control chromosomes in the GnomAD database, including 67,480 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 0.94 (67480 hom., cov: 32)
• Consequence: IREB2 NM_004136.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.729
• Publications: 2 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IREB2	NM_004136.4	c.2782-274G>A		intron_variant	Intron 21 of 21	ENST00000258886.13	NP_004127.2
IREB2	NM_001320942.2	c.2611-274G>A		intron_variant	Intron 21 of 21		NP_001307871.2
IREB2	NM_001354994.2	c.2611-274G>A		intron_variant	Intron 21 of 21		NP_001341923.2
IREB2	NM_001320941.2	c.2032-274G>A		intron_variant	Intron 20 of 20		NP_001307870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IREB2	ENST00000258886.13	c.2782-274G>A		intron_variant	Intron 21 of 21	1	NM_004136.4	ENSP00000258886.8
IREB2	ENST00000558570.5	n.*2049-274G>A		intron_variant	Intron 20 of 20	1		ENSP00000454063.1

Frequencies

GnomAD3 genomes AF: 0.936 AC: 142434 AN: 152128 Hom.: 67437 Cov.: 32

Gnomad AFR AF: 0.779

Gnomad AMI AF: 0.990

Gnomad AMR AF: 0.977

Gnomad ASJ AF: 0.983

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.984

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.958

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

GnomAD4 genome AF: 0.936 AC: 142540 AN: 152246 Hom.: 67480 Cov.: 32 AF XY: 0.939 AC XY: 69912 AN XY: 74450

African (AFR) AF: 0.780 AC: 32358 AN: 41500

American (AMR) AF: 0.977 AC: 14942 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.983 AC: 3413 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5182 AN: 5182

South Asian (SAS) AF: 1.00 AC: 4830 AN: 4830

European-Finnish (FIN) AF: 1.00 AC: 10622 AN: 10622

Middle Eastern (MID) AF: 0.986 AC: 290 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67979 AN: 68036

Other (OTH) AF: 0.959 AC: 2021 AN: 2108

Alfa AF: 0.950 Hom.: 14557

Bravo AF: 0.927

Asia WGS AF: 0.989 AC: 3439 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.8
DANN	Benign	0.69
PhyloP100		-0.73
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: rs9920411; hg19: chr15-78790101;