15-78474287-C-T

Position:

• chr15-78474287-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000258886.13(IREB2):​c.1023+906C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.506 in 151,972 control chromosomes in the GnomAD database, including 20,815 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 0.51 (20815 hom., cov: 32)
  • Exomes 𝑓: 0.25 (0 hom.)
• Consequence: IREB2 ENST00000258886.13 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.25

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=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.613 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IREB2	NM_004136.4	c.1023+906C>T		intron_variant		ENST00000258886.13	NP_004127.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IREB2	ENST00000560440.5	c.*897C>T		3_prime_UTR_variant	8/8	1		ENSP00000452938
IREB2	ENST00000258886.13	c.1023+906C>T		intron_variant		1	NM_004136.4	ENSP00000258886	P1
IREB2	ENST00000558570.5	c.*290+906C>T		intron_variant, NMD_transcript_variant		1		ENSP00000454063

Frequencies

GnomAD3 genomes AF: 0.506 AC: 76801 AN: 151850 Hom.: 20803 Cov.: 32

Gnomad AFR AF: 0.304

Gnomad AMI AF: 0.685

Gnomad AMR AF: 0.498

Gnomad ASJ AF: 0.552

Gnomad EAS AF: 0.464

Gnomad SAS AF: 0.479

Gnomad FIN AF: 0.586

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.618

Gnomad OTH AF: 0.516

GnomAD4 exome AF: 0.250 AC: 1 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

Gnomad4 FIN exome AF: 0.500

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.506 AC: 76835 AN: 151968 Hom.: 20815 Cov.: 32 AF XY: 0.505 AC XY: 37533 AN XY: 74278

Gnomad4 AFR AF: 0.304

Gnomad4 AMR AF: 0.497

Gnomad4 ASJ AF: 0.552

Gnomad4 EAS AF: 0.465

Gnomad4 SAS AF: 0.479

Gnomad4 FIN AF: 0.586

Gnomad4 NFE AF: 0.618

Gnomad4 OTH AF: 0.511

Alfa AF: 0.541 Hom.: 3978

Bravo AF: 0.492

Asia WGS AF: 0.432 AC: 1504 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.0060
DANN	Benign	0.45

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: rs1504549; hg19: chr15-78766629;