rs2004640

Variant names:

• chr7-128938247-T-G
• rs2004640
• NM_001098629.3:c.-12+198T>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PVS1_Moderate BA1

The NM_032643.5(IRF5):​c.-12+2T>G variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.526 in 151,736 control chromosomes in the GnomAD database, including 21,339 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 0.53 (21302 hom., cov: 32)
  • Exomes 𝑓: 0.56 (37 hom.)
• Consequence: IRF5 NM_032643.5 splice_donor, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.802
• Publications: 227 publications found

Genes affected

IRF5 (HGNC:6120): (interferon regulatory factor 5) This gene encodes a member of the interferon regulatory factor (IRF) family, a group of transcription factors with diverse roles, including virus-mediated activation of interferon, and modulation of cell growth, differentiation, apoptosis, and immune system activity. Members of the IRF family are characterized by a conserved N-terminal DNA-binding domain containing tryptophan (W) repeats. Alternative promoter use and alternative splicing result in multiple transcript variants, and a 30-nt indel polymorphism (SNP rs60344245) can result in loss of a 10-aa segment. [provided by RefSeq, Dec 2016]

IRF5 Gene-Disease associations (from GenCC):

• systemic lupus erythematosus

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.019372078 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.2, offset of 18, new splice context is: aggGTgcgc. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.701 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032643.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF5	NM_001098629.3	MANE Select	c.-12+198T>G		intron	N/A	NP_001092099.1
	IRF5	NM_001347928.2		c.-12+982T>G		intron	N/A	NP_001334857.1
	IRF5	NM_001098630.3		c.-12+198T>G		intron	N/A	NP_001092100.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF5	ENST00000357234.10	TSL:1 MANE Select	c.-12+198T>G		intron	N/A	ENSP00000349770.5
	IRF5	ENST00000402030.6	TSL:1	c.-12+198T>G		intron	N/A	ENSP00000385352.2
	IRF5	ENST00000477535.5	TSL:1	c.-12+198T>G		intron	N/A	ENSP00000419950.1

Frequencies

GnomAD3 genomes AF: 0.526 AC: 79628 AN: 151418 Hom.: 21275 Cov.: 32

Gnomad AFR AF: 0.584

Gnomad AMI AF: 0.510

Gnomad AMR AF: 0.542

Gnomad ASJ AF: 0.384

Gnomad EAS AF: 0.721

Gnomad SAS AF: 0.494

Gnomad FIN AF: 0.485

Gnomad MID AF: 0.376

Gnomad NFE AF: 0.490

Gnomad OTH AF: 0.491

GnomAD4 exome AF: 0.559 AC: 113 AN: 202 Hom.: 37 Cov.: 0 AF XY: 0.549 AC XY: 89 AN XY: 162

African (AFR) AF: 0.750 AC: 3 AN: 4

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.833 AC: 10 AN: 12

South Asian (SAS) AF: 0.750 AC: 3 AN: 4

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.547 AC: 94 AN: 172

Other (OTH) AF: 0.375 AC: 3 AN: 8

GnomAD4 genome AF: 0.526 AC: 79705 AN: 151534 Hom.: 21302 Cov.: 32 AF XY: 0.529 AC XY: 39171 AN XY: 74052

African (AFR) AF: 0.584 AC: 24115 AN: 41320

American (AMR) AF: 0.543 AC: 8284 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.384 AC: 1331 AN: 3466

East Asian (EAS) AF: 0.720 AC: 3692 AN: 5126

South Asian (SAS) AF: 0.493 AC: 2376 AN: 4818

European-Finnish (FIN) AF: 0.485 AC: 5088 AN: 10494

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.490 AC: 33208 AN: 67746

Other (OTH) AF: 0.494 AC: 1041 AN: 2106

Alfa AF: 0.377 Hom.: 1334

Bravo AF: 0.531

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.9
PhyloP100		-0.80
PromoterAI		0.10	Neutral

Splicing

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

Other links and lift over

dbSNP: rs2004640; hg19: chr7-128578301;