chr15-78450412-C-A

Variant names:

• chr15-78450412-C-A
• rs10519198
• NM_004136.4:c.106+10531C>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.106+10531C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.365 in 152,106 control chromosomes in the GnomAD database, including 10,851 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 (10851 hom., cov: 33)
• Consequence: IREB2 NM_004136.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.745
• Publications: 22 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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.461 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IREB2	NM_004136.4	MANE Select	c.106+10531C>A		intron	N/A	NP_004127.2
	IREB2	NM_001320942.2		c.-66+10531C>A		intron	N/A	NP_001307871.2
	IREB2	NM_001354994.2		c.-66+10531C>A		intron	N/A	NP_001341923.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IREB2	ENST00000258886.13	TSL:1 MANE Select	c.106+10531C>A		intron	N/A	ENSP00000258886.8
	IREB2	ENST00000560440.5	TSL:1	c.106+10531C>A		intron	N/A	ENSP00000452938.1
	IREB2	ENST00000558570.5	TSL:1	n.106+10531C>A		intron	N/A	ENSP00000454063.1

Frequencies

GnomAD3 genomes AF: 0.365 AC: 55488 AN: 151988 Hom.: 10849 Cov.: 33

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.480

Gnomad AMR AF: 0.328

Gnomad ASJ AF: 0.403

Gnomad EAS AF: 0.476

Gnomad SAS AF: 0.407

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.434

Gnomad OTH AF: 0.370

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

GnomAD4 genome AF: 0.365 AC: 55509 AN: 152106 Hom.: 10851 Cov.: 33 AF XY: 0.367 AC XY: 27294 AN XY: 74366

African (AFR) AF: 0.225 AC: 9357 AN: 41502

American (AMR) AF: 0.327 AC: 5002 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.403 AC: 1396 AN: 3462

East Asian (EAS) AF: 0.476 AC: 2467 AN: 5178

South Asian (SAS) AF: 0.406 AC: 1957 AN: 4826

European-Finnish (FIN) AF: 0.432 AC: 4560 AN: 10566

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

European-Non Finnish (NFE) AF: 0.434 AC: 29471 AN: 67964

Other (OTH) AF: 0.373 AC: 786 AN: 2110

Alfa AF: 0.404 Hom.: 41512

Bravo AF: 0.354

Asia WGS AF: 0.400 AC: 1389 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.75
DANN	Benign	0.89
PhyloP100		-0.74
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: rs10519198; hg19: chr15-78742754;