rs2004640

Variant names:

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

Variant summary

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

The NM_001098629.3(IRF5):​c.-12+198T>G variant causes a 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_001098629.3 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.701 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF5	NM_001098629.3	c.-12+198T>G		intron_variant	Intron 1 of 8	ENST00000357234.10	NP_001092099.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF5	ENST00000357234.10	c.-12+198T>G		intron_variant	Intron 1 of 8	1	NM_001098629.3	ENSP00000349770.5

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 v4.3

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;