rs1964678

Variant names:

• chr15-78461658-A-G
• rs1964678
• NM_004136.4:c.107-1264A>G

Your query was ambiguous. Multiple possible variants found:

• chr15-78461658-A-G
• chr15-78461658-A-T

Variant summary

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

The NM_004136.4(IREB2):​c.107-1264A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.509 in 151,954 control chromosomes in the GnomAD database, including 21,072 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 0.51 (21072 hom., cov: 31)
• Consequence: IREB2 NM_004136.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.08
• Publications: 21 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=-1.02).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.616 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IREB2	NM_004136.4	c.107-1264A>G		intron_variant	Intron 2 of 21	ENST00000258886.13	NP_004127.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IREB2	ENST00000258886.13	c.107-1264A>G		intron_variant	Intron 2 of 21	1	NM_004136.4	ENSP00000258886.8

Frequencies

GnomAD3 genomes AF: 0.509 AC: 77311 AN: 151836 Hom.: 21062 Cov.: 31

Gnomad AFR AF: 0.306

Gnomad AMI AF: 0.681

Gnomad AMR AF: 0.500

Gnomad ASJ AF: 0.565

Gnomad EAS AF: 0.472

Gnomad SAS AF: 0.497

Gnomad FIN AF: 0.586

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.621

Gnomad OTH AF: 0.520

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

GnomAD4 genome AF: 0.509 AC: 77338 AN: 151954 Hom.: 21072 Cov.: 31 AF XY: 0.509 AC XY: 37779 AN XY: 74242

African (AFR) AF: 0.306 AC: 12671 AN: 41450

American (AMR) AF: 0.500 AC: 7621 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.565 AC: 1958 AN: 3468

East Asian (EAS) AF: 0.473 AC: 2441 AN: 5166

South Asian (SAS) AF: 0.498 AC: 2393 AN: 4806

European-Finnish (FIN) AF: 0.586 AC: 6197 AN: 10568

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.621 AC: 42195 AN: 67938

Other (OTH) AF: 0.515 AC: 1084 AN: 2104

Alfa AF: 0.547 Hom.: 10565

Bravo AF: 0.496

Asia WGS AF: 0.446 AC: 1554 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.27
DANN	Benign	0.17
PhyloP100		-1.1
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: rs1964678; hg19: chr15-78754000;