15-78497146-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_004136.4(IREB2):c.2616C>T(p.Ala872Ala) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.355

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
IREB2	NM_004136.4 link	c.2616C>T	p.Ala872Ala	synonymous_variant	Exon 21 of 22	ENST00000258886.13	NP_004127.2	P48200-1D3DW85
IREB2	NM_001320942.2 link	c.2445C>T	p.Ala815Ala	synonymous_variant	Exon 21 of 22		NP_001307871.2
IREB2	NM_001354994.2 link	c.2445C>T	p.Ala815Ala	synonymous_variant	Exon 21 of 22		NP_001341923.2
IREB2	NM_001320941.2 link	c.1866C>T	p.Ala622Ala	synonymous_variant	Exon 20 of 21		NP_001307870.2	P48200

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
IREB2	ENST00000258886.13 link	c.2616C>T	p.Ala872Ala	synonymous_variant	Exon 21 of 22	1	NM_004136.4	ENSP00000258886.8	P48200-1
IREB2	ENST00000558570.5 link	n.*1883C>T		non_coding_transcript_exon_variant	Exon 20 of 21	1		ENSP00000454063.1	H0YNL8
IREB2	ENST00000558570.5 link	n.*1883C>T		3_prime_UTR_variant	Exon 20 of 21	1		ENSP00000454063.1	H0YNL8
IREB2	ENST00000559091.1 link	c.75C>T	p.Ala25Ala	synonymous_variant	Exon 2 of 2	3		ENSP00000453863.1	H0YN46

Frequencies

GnomAD3 genomes

AF:

0.506

AC:

76752

AN:

151660

Hom.:

20798

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.585

AC XY:

424127

AN XY:

725504

show subpopulations

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.:

AF XY:

0.506

AC XY:

37483

AN XY:

74138

show subpopulations

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:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia

Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

IREB2-related disorder

Benign:1

Oct 30, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over