rs2004640

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -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

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]

ACMG classification

Verdict is Likely_benign. Variant got -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.

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

Gnomad4 AFR exome AF: 0.750

Gnomad4 EAS exome AF: 0.833

Gnomad4 SAS exome AF: 0.750

Gnomad4 NFE exome AF: 0.547

Gnomad4 OTH exome AF: 0.375

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

Gnomad4 AFR AF: 0.584

Gnomad4 AMR AF: 0.543

Gnomad4 ASJ AF: 0.384

Gnomad4 EAS AF: 0.720

Gnomad4 SAS AF: 0.493

Gnomad4 FIN AF: 0.485

Gnomad4 NFE AF: 0.490

Gnomad4 OTH AF: 0.494

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2004640; hg19: chr7-128578301;