chr15-78453365-C-T

Variant names:

• chr15-78453365-C-T
• rs2656069
• NM_004136.4:c.107-9557C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004136.4(IREB2):​c.107-9557C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.767 in 152,078 control chromosomes in the GnomAD database, including 44,992 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 0.77 (44992 hom., cov: 31)
• Consequence: IREB2 NM_004136.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.655
• Publications: 28 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: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.799 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.107-9557C>T		intron	N/A	NP_004127.2	P48200-1
	IREB2	NM_001320942.2		c.-65-9557C>T		intron	N/A	NP_001307871.2
	IREB2	NM_001354994.2		c.-65-9557C>T		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.107-9557C>T		intron	N/A	ENSP00000258886.8	P48200-1
	IREB2	ENST00000560440.5	TSL:1	c.107-9557C>T		intron	N/A	ENSP00000452938.1	P48200-2
	IREB2	ENST00000558570.5	TSL:1	n.107-9557C>T		intron	N/A	ENSP00000454063.1	H0YNL8

Frequencies

GnomAD3 genomes AF: 0.767 AC: 116597 AN: 151960 Hom.: 44943 Cov.: 31

Gnomad AFR AF: 0.806

Gnomad AMI AF: 0.852

Gnomad AMR AF: 0.651

Gnomad ASJ AF: 0.793

Gnomad EAS AF: 0.729

Gnomad SAS AF: 0.648

Gnomad FIN AF: 0.750

Gnomad MID AF: 0.705

Gnomad NFE AF: 0.782

Gnomad OTH AF: 0.757

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

GnomAD4 genome AF: 0.767 AC: 116698 AN: 152078 Hom.: 44992 Cov.: 31 AF XY: 0.764 AC XY: 56762 AN XY: 74338

African (AFR) AF: 0.806 AC: 33453 AN: 41482

American (AMR) AF: 0.651 AC: 9947 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.793 AC: 2750 AN: 3470

East Asian (EAS) AF: 0.730 AC: 3778 AN: 5176

South Asian (SAS) AF: 0.649 AC: 3123 AN: 4812

European-Finnish (FIN) AF: 0.750 AC: 7919 AN: 10564

Middle Eastern (MID) AF: 0.710 AC: 206 AN: 290

European-Non Finnish (NFE) AF: 0.782 AC: 53151 AN: 67976

Other (OTH) AF: 0.756 AC: 1596 AN: 2110

Alfa AF: 0.768 Hom.: 22896

Bravo AF: 0.765

Asia WGS AF: 0.665 AC: 2312 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.61
DANN	Benign	0.63
PhyloP100		-0.66
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: rs2656069; hg19: chr15-78745707;