15-78497146-C-T

Variant names:

• chr15-78497146-C-T
• rs13180
• NM_004136.4:c.2616C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.355
• Publications: 105 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: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004136.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IREB2	NM_004136.4	MANE Select	c.2616C>T	p.Ala872Ala	synonymous	Exon 21 of 22	NP_004127.2	P48200-1
	IREB2	NM_001320942.2		c.2445C>T	p.Ala815Ala	synonymous	Exon 21 of 22	NP_001307871.2
	IREB2	NM_001354994.2		c.2445C>T	p.Ala815Ala	synonymous	Exon 21 of 22	NP_001341923.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IREB2	ENST00000258886.13	TSL:1 MANE Select	c.2616C>T	p.Ala872Ala	synonymous	Exon 21 of 22	ENSP00000258886.8	P48200-1
	IREB2	ENST00000558570.5	TSL:1	n.*1883C>T		non_coding_transcript_exon	Exon 20 of 21	ENSP00000454063.1	H0YNL8
	IREB2	ENST00000558570.5	TSL:1	n.*1883C>T		3_prime_UTR	Exon 20 of 21	ENSP00000454063.1	H0YNL8

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

GnomAD2 exomes AF: 0.545 AC: 136803 AN: 251162 AF XY: 0.549

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 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

African (AFR) AF: 0.293 AC: 9779 AN: 33432

American (AMR) AF: 0.493 AC: 22027 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.532 AC: 13876 AN: 26096

East Asian (EAS) AF: 0.436 AC: 17273 AN: 39648

South Asian (SAS) AF: 0.487 AC: 42004 AN: 86174

European-Finnish (FIN) AF: 0.582 AC: 31078 AN: 53402

Middle Eastern (MID) AF: 0.547 AC: 3149 AN: 5762

European-Non Finnish (NFE) AF: 0.616 AC: 683302 AN: 1108534

Other (OTH) AF: 0.553 AC: 33309 AN: 60248

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

African (AFR) AF: 0.304 AC: 12579 AN: 41370

American (AMR) AF: 0.496 AC: 7557 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.551 AC: 1909 AN: 3464

East Asian (EAS) AF: 0.466 AC: 2391 AN: 5128

South Asian (SAS) AF: 0.481 AC: 2316 AN: 4812

European-Finnish (FIN) AF: 0.586 AC: 6181 AN: 10540

Middle Eastern (MID) AF: 0.541 AC: 159 AN: 294

European-Non Finnish (NFE) AF: 0.618 AC: 41995 AN: 67916

Other (OTH) AF: 0.511 AC: 1078 AN: 2108

Alfa AF: 0.575 Hom.: 129042

Bravo AF: 0.492

Asia WGS AF: 0.433 AC: 1509 AN: 3478

EpiCase AF: 0.619

EpiControl AF: 0.625

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	IREB2-related disorder (1)
-	-	1	Neurodegeneration, early-onset, with choreoathetoid movements and microcytic anemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	6.9
DANN	Benign	0.68
PhyloP100		-0.35
Mutation Taster		=90/10	polymorphism (auto)

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

Other links and lift over

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