chr15-78482334-A-G

Variant names:

• chr15-78482334-A-G
• rs10851906
• NM_004136.4:c.1297-984A>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.1297-984A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 152,218 control chromosomes in the GnomAD database, including 3,994 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 0.22 (3994 hom., cov: 32)
• Consequence: IREB2 NM_004136.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.819
• Publications: 20 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=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.338 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IREB2	NM_004136.4	c.1297-984A>G		intron_variant	Intron 10 of 21	ENST00000258886.13	NP_004127.2
IREB2	NM_001320942.2	c.1126-984A>G		intron_variant	Intron 10 of 21		NP_001307871.2
IREB2	NM_001354994.2	c.1126-984A>G		intron_variant	Intron 10 of 21		NP_001341923.2
IREB2	NM_001320941.2	c.547-984A>G		intron_variant	Intron 9 of 20		NP_001307870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IREB2	ENST00000258886.13	c.1297-984A>G		intron_variant	Intron 10 of 21	1	NM_004136.4	ENSP00000258886.8
IREB2	ENST00000558570.5	n.*564-984A>G		intron_variant	Intron 9 of 20	1		ENSP00000454063.1

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33410 AN: 152100 Hom.: 3989 Cov.: 32

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.148

Gnomad AMR AF: 0.345

Gnomad ASJ AF: 0.207

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.350

Gnomad FIN AF: 0.251

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.238

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

GnomAD4 genome AF: 0.220 AC: 33419 AN: 152218 Hom.: 3994 Cov.: 32 AF XY: 0.224 AC XY: 16658 AN XY: 74394

African (AFR) AF: 0.146 AC: 6082 AN: 41534

American (AMR) AF: 0.346 AC: 5286 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 718 AN: 3470

East Asian (EAS) AF: 0.276 AC: 1428 AN: 5182

South Asian (SAS) AF: 0.350 AC: 1687 AN: 4824

European-Finnish (FIN) AF: 0.251 AC: 2656 AN: 10594

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.218 AC: 14834 AN: 67996

Other (OTH) AF: 0.239 AC: 505 AN: 2116

Alfa AF: 0.219 Hom.: 859

Bravo AF: 0.220

Asia WGS AF: 0.333 AC: 1157 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.23
DANN	Benign	0.47
PhyloP100		-0.82
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: rs10851906; hg19: chr15-78774676;