15-78439782-AT-ATTT

Variant names:

• chr15-78439782-A-ATT
• rs533778908
• NM_004136.4:c.20-5_20-4dupTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004136.4(IREB2):​c.20-5_20-4dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000848 in 1,297,646 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000085 (0 hom.)
• Consequence: IREB2 NM_004136.4 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.632
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.20-5_20-4dupTT		splice_region intron	N/A	NP_004127.2	P48200-1
	IREB2	NM_001320942.2		c.-152-5_-152-4dupTT		splice_region intron	N/A	NP_001307871.2
	IREB2	NM_001354994.2		c.-152-5_-152-4dupTT		splice_region 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.20-13_20-12insTT		intron	N/A	ENSP00000258886.8	P48200-1
	IREB2	ENST00000560440.5	TSL:1	c.20-13_20-12insTT		intron	N/A	ENSP00000452938.1	P48200-2
	IREB2	ENST00000558570.5	TSL:1	n.20-13_20-12insTT		intron	N/A	ENSP00000454063.1	H0YNL8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000848 AC: 11 AN: 1297646 Hom.: 0 Cov.: 20 AF XY: 0.00000924 AC XY: 6 AN XY: 649302

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000345 AC: 1 AN: 29014

American (AMR) AF: 0.0000283 AC: 1 AN: 35278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24162

East Asian (EAS) AF: 0.00 AC: 0 AN: 37834

South Asian (SAS) AF: 0.0000399 AC: 3 AN: 75250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51888

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5280

European-Non Finnish (NFE) AF: 0.00000610 AC: 6 AN: 984262

Other (OTH) AF: 0.00 AC: 0 AN: 54678

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.63

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs533778908; hg19: chr15-78732124;