15-78439782-AT-ATT

Variant names:

• chr15-78439782-A-AT
• rs533778908
• NM_004136.4:c.20-4dupT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_004136.4(IREB2):​c.20-4dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00212 in 1,436,622 control chromosomes in the GnomAD database, including 1 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (1 hom.)
• Consequence: IREB2 NM_004136.4 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:2
• 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 15-78439782-A-AT is Benign according to our data. Variant chr15-78439782-A-AT is described in ClinVar as Benign. ClinVar VariationId is 3021263.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Frequencies

GnomAD3 genomes AF: 0.000271 AC: 41 AN: 151528 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000510

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00105

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00182 AC: 345 AN: 189248 AF XY: 0.00162

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00270

Gnomad ASJ exome AF: 0.000661

Gnomad EAS exome AF: 0.00225

Gnomad FIN exome AF: 0.00366

Gnomad NFE exome AF: 0.00133

Gnomad OTH exome AF: 0.00177

GnomAD4 exome AF: 0.00234 AC: 3004 AN: 1285094 Hom.: 1 Cov.: 20 AF XY: 0.00222 AC XY: 1431 AN XY: 643180

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

African (AFR) AF: 0.00261 AC: 75 AN: 28736

American (AMR) AF: 0.00146 AC: 51 AN: 35004

Ashkenazi Jewish (ASJ) AF: 0.000708 AC: 17 AN: 24016

East Asian (EAS) AF: 0.00125 AC: 47 AN: 37580

South Asian (SAS) AF: 0.00189 AC: 141 AN: 74642

European-Finnish (FIN) AF: 0.00297 AC: 153 AN: 51528

Middle Eastern (MID) AF: 0.000953 AC: 5 AN: 5244

European-Non Finnish (NFE) AF: 0.00247 AC: 2408 AN: 974192

Other (OTH) AF: 0.00198 AC: 107 AN: 54152

⚠️ 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 AF: 0.000271 AC: 41 AN: 151528 Hom.: 0 Cov.: 32 AF XY: 0.000324 AC XY: 24 AN XY: 73992

African (AFR) AF: 0.000510 AC: 21 AN: 41208

American (AMR) AF: 0.00 AC: 0 AN: 15192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4802

European-Finnish (FIN) AF: 0.00105 AC: 11 AN: 10494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67886

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.00400 Hom.: 0

Bravo AF: 0.000204

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	IREB2-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.63
Mutation Taster		=100/0	polymorphism

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: rs533778908; hg19: chr15-78732124; COSMIC: COSV51925983;