rs10519198

Positions:

• chr15-78450412-C-A
• chr15-78450412-C-G

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IREB2	NM_004136.4	c.106+10531C>A		intron_variant		ENST00000258886.13	NP_004127.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IREB2	ENST00000258886.13	c.106+10531C>A		intron_variant		1	NM_004136.4	ENSP00000258886	P1

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

Gnomad4 AFR AF: 0.225

Gnomad4 AMR AF: 0.327

Gnomad4 ASJ AF: 0.403

Gnomad4 EAS AF: 0.476

Gnomad4 SAS AF: 0.406

Gnomad4 FIN AF: 0.432

Gnomad4 NFE AF: 0.434

Gnomad4 OTH AF: 0.373

Alfa AF: 0.414 Hom.: 27433

Bravo AF: 0.354

Asia WGS AF: 0.400 AC: 1389 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.75
DANN	Benign	0.89

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

Publications

LitVar

Other links and lift over

dbSNP: rs10519198; hg19: chr15-78742754;