rs16969899

Variant names:

• chr15-78489984-T-G
• rs16969899
• NM_004136.4:c.2077-438T>G

Variant summary

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

The NM_004136.4(IREB2):​c.2077-438T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 152,270 control chromosomes in the GnomAD database, including 1,992 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 0.16 (1992 hom., cov: 32)
• Consequence: IREB2 NM_004136.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.838
• Publications: 8 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: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IREB2	NM_004136.4	c.2077-438T>G		intron_variant	Intron 16 of 21	ENST00000258886.13	NP_004127.2
IREB2	NM_001320942.2	c.1906-438T>G		intron_variant	Intron 16 of 21		NP_001307871.2
IREB2	NM_001354994.2	c.1906-438T>G		intron_variant	Intron 16 of 21		NP_001341923.2
IREB2	NM_001320941.2	c.1327-438T>G		intron_variant	Intron 15 of 20		NP_001307870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IREB2	ENST00000258886.13	c.2077-438T>G		intron_variant	Intron 16 of 21	1	NM_004136.4	ENSP00000258886.8
IREB2	ENST00000558570.5	n.*1344-438T>G		intron_variant	Intron 15 of 20	1		ENSP00000454063.1

Frequencies

GnomAD3 genomes AF: 0.159 AC: 24235 AN: 152152 Hom.: 1986 Cov.: 32

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.157

Gnomad AMR AF: 0.114

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.164

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.168

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

GnomAD4 genome AF: 0.159 AC: 24270 AN: 152270 Hom.: 1992 Cov.: 32 AF XY: 0.159 AC XY: 11815 AN XY: 74464

African (AFR) AF: 0.169 AC: 7021 AN: 41530

American (AMR) AF: 0.114 AC: 1743 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 713 AN: 3472

East Asian (EAS) AF: 0.148 AC: 770 AN: 5194

South Asian (SAS) AF: 0.161 AC: 775 AN: 4828

European-Finnish (FIN) AF: 0.164 AC: 1737 AN: 10602

Middle Eastern (MID) AF: 0.119 AC: 35 AN: 294

European-Non Finnish (NFE) AF: 0.161 AC: 10966 AN: 68018

Other (OTH) AF: 0.174 AC: 367 AN: 2114

Alfa AF: 0.150 Hom.: 348

Bravo AF: 0.157

Asia WGS AF: 0.168 AC: 583 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.51
DANN	Benign	0.75
PhyloP100		-0.84
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: rs16969899; hg19: chr15-78782326;