rs41298401

Variant names:

• chr7-128938253-C-G
• rs41298401
• NM_001098629.3:c.-12+204C>G

Variant summary

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

The NM_032643.5(IRF5):​c.-12+8C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0361 in 152,378 control chromosomes in the GnomAD database, including 284 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.036 (284 hom., cov: 31)
  • Exomes 𝑓: 0.043 (0 hom.)
• Consequence: IRF5 NM_032643.5 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.185
• Publications: 8 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=-0.74).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.217 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF5	NM_001098629.3	MANE Select	c.-12+204C>G		intron	N/A	NP_001092099.1	Q13568-2
	IRF5	NM_001347928.2		c.-12+988C>G		intron	N/A	NP_001334857.1	Q13568-2
	IRF5	NM_001098630.3		c.-12+204C>G		intron	N/A	NP_001092100.1	Q13568-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF5	ENST00000357234.10	TSL:1 MANE Select	c.-12+204C>G		intron	N/A	ENSP00000349770.5	Q13568-2
	IRF5	ENST00000402030.6	TSL:1	c.-12+204C>G		intron	N/A	ENSP00000385352.2	Q13568-1
	IRF5	ENST00000477535.5	TSL:1	c.-12+204C>G		intron	N/A	ENSP00000419950.1	Q13568-5

Frequencies

GnomAD3 genomes AF: 0.0361 AC: 5486 AN: 152098 Hom.: 285 Cov.: 31

Gnomad AFR AF: 0.0682

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0330

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.0707

Gnomad FIN AF: 0.0138

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00544

Gnomad OTH AF: 0.0316

GnomAD4 exome AF: 0.0427 AC: 7 AN: 164 Hom.: 0 Cov.: 0 AF XY: 0.0431 AC XY: 5 AN XY: 116

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

East Asian (EAS) AF: 0.250 AC: 2 AN: 8

South Asian (SAS) AF: 0.250 AC: 1 AN: 4

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

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0147 AC: 2 AN: 136

Other (OTH) AF: 0.200 AC: 2 AN: 10

GnomAD4 genome AF: 0.0361 AC: 5495 AN: 152214 Hom.: 284 Cov.: 31 AF XY: 0.0383 AC XY: 2848 AN XY: 74432

African (AFR) AF: 0.0682 AC: 2834 AN: 41548

American (AMR) AF: 0.0327 AC: 501 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3470

East Asian (EAS) AF: 0.228 AC: 1171 AN: 5136

South Asian (SAS) AF: 0.0713 AC: 344 AN: 4822

European-Finnish (FIN) AF: 0.0138 AC: 146 AN: 10616

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.00544 AC: 370 AN: 68000

Other (OTH) AF: 0.0332 AC: 70 AN: 2108

Alfa AF: 0.0221 Hom.: 19

Bravo AF: 0.0407

Asia WGS AF: 0.145 AC: 504 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	11
DANN	Benign	0.69
PhyloP100		0.18
PromoterAI		0.087	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs41298401; hg19: chr7-128578307; COSMIC: COSV107218922;