rs13180

chr15-78497146-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004136.4(IREB2):c.2616C>T(p.Ala872=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.579 in 1,609,776 control chromosomes in the GnomAD database, including 276,179 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (20810 hom., cov: 31)
  • Exomes 𝑓: 0.59 (255369 hom.)
• Consequence: IREB2 NM_004136.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.355

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 15-78497146-C-T is Benign according to our data. Variant chr15-78497146-C-T is described in ClinVar as [Benign]. Clinvar id is 1300043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.355 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.613 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IREB2	NM_004136.4	c.2616C>T	p.Ala872=	synonymous_variant	21/22	ENST00000258886.13
IREB2	NM_001320942.2	c.2445C>T	p.Ala815=	synonymous_variant	21/22
IREB2	NM_001354994.2	c.2445C>T	p.Ala815=	synonymous_variant	21/22
IREB2	NM_001320941.2	c.1866C>T	p.Ala622=	synonymous_variant	20/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IREB2	ENST00000258886.13	c.2616C>T	p.Ala872=	synonymous_variant	21/22	1	NM_004136.4	P1
IREB2	ENST00000558570.5	c.*1883C>T		3_prime_UTR_variant, NMD_transcript_variant	20/21	1
IREB2	ENST00000559091.1	c.78C>T	p.Ala26=	synonymous_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.506 AC: 76752 AN: 151660 Hom.: 20798 Cov.: 31

Gnomad AFR AF: 0.304

Gnomad AMI AF: 0.688

Gnomad AMR AF: 0.496

Gnomad ASJ AF: 0.551

Gnomad EAS AF: 0.465

Gnomad SAS AF: 0.481

Gnomad FIN AF: 0.586

Gnomad MID AF: 0.541

Gnomad NFE AF: 0.618

Gnomad OTH AF: 0.516

GnomAD3 exomes AF: 0.545 AC: 136803 AN: 251162 Hom.: 38338 AF XY: 0.549 AC XY: 74607 AN XY: 135786

Gnomad AFR exome AF: 0.298

Gnomad AMR exome AF: 0.498

Gnomad ASJ exome AF: 0.529

Gnomad EAS exome AF: 0.480

Gnomad SAS exome AF: 0.487

Gnomad FIN exome AF: 0.574

Gnomad NFE exome AF: 0.615

Gnomad OTH exome AF: 0.559

GnomAD4 exome AF: 0.587 AC: 855797 AN: 1457998 Hom.: 255369 Cov.: 38 AF XY: 0.585 AC XY: 424127 AN XY: 725504

Gnomad4 AFR exome AF: 0.293

Gnomad4 AMR exome AF: 0.493

Gnomad4 ASJ exome AF: 0.532

Gnomad4 EAS exome AF: 0.436

Gnomad4 SAS exome AF: 0.487

Gnomad4 FIN exome AF: 0.582

Gnomad4 NFE exome AF: 0.616

Gnomad4 OTH exome AF: 0.553

GnomAD4 genome AF: 0.506 AC: 76786 AN: 151778 Hom.: 20810 Cov.: 31 AF XY: 0.506 AC XY: 37483 AN XY: 74138

Gnomad4 AFR AF: 0.304

Gnomad4 AMR AF: 0.496

Gnomad4 ASJ AF: 0.551

Gnomad4 EAS AF: 0.466

Gnomad4 SAS AF: 0.481

Gnomad4 FIN AF: 0.586

Gnomad4 NFE AF: 0.618

Gnomad4 OTH AF: 0.511

Alfa AF: 0.586 Hom.: 70564

Bravo AF: 0.492

Asia WGS AF: 0.433 AC: 1509 AN: 3478

EpiCase AF: 0.619

EpiControl AF: 0.625

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

IREB2-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 30, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
Cadd	Benign	6.9
Dann	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs13180; hg19: chr15-78789488; COSMIC: COSV51921389;