15-78462943-G-A

Variant names:

• chr15-78462943-G-A
• rs1567168999
• NM_004136.4:c.128G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004136.4(IREB2):​c.128G>A​(p.Arg43Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,457,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IREB2 NM_004136.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.64
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.128G>A	p.Arg43Gln	missense	Exon 3 of 22	NP_004127.2	P48200-1
	IREB2	NM_001320943.2		c.128G>A	p.Arg43Gln	missense	Exon 3 of 8	NP_001307872.1	P48200-2
	IREB2	NM_001320942.2		c.-44G>A		5_prime_UTR	Exon 3 of 22	NP_001307871.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IREB2	ENST00000258886.13	TSL:1 MANE Select	c.128G>A	p.Arg43Gln	missense	Exon 3 of 22	ENSP00000258886.8	P48200-1
	IREB2	ENST00000560440.5	TSL:1	c.128G>A	p.Arg43Gln	missense	Exon 3 of 8	ENSP00000452938.1	P48200-2
	IREB2	ENST00000558570.5	TSL:1	n.128G>A		non_coding_transcript_exon	Exon 3 of 21	ENSP00000454063.1	H0YNL8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 248210 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000886

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457710 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725388

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

African (AFR) AF: 0.00 AC: 0 AN: 33256

American (AMR) AF: 0.0000228 AC: 1 AN: 43822

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25976

East Asian (EAS) AF: 0.00 AC: 0 AN: 39536

South Asian (SAS) AF: 0.00 AC: 0 AN: 85578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110266

Other (OTH) AF: 0.00 AC: 0 AN: 60216

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	36
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.038	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.61	T
MutationAssessor	Pathogenic	4.0	H
PhyloP100		9.6
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.90		Gain of catalytic residue at R43 (P = 0.1587)
MVP		0.75
MPC		1.1
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.71
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		1.0		Position offset: 2
DS_AL_spliceai		0.54		Position offset: -21

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

Other links and lift over

dbSNP: rs1567168999; hg19: chr15-78755285;