rs750603767

Variant names:

• chr7-128947323-C-T
• rs750603767
• NM_001098629.3:c.575C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001098629.3(IRF5):​c.575C>T​(p.Pro192Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. P192P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000050 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: IRF5 NM_001098629.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0550
• Publications: 1 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08165297).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098629.3. 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.575C>T	p.Pro192Leu	missense	Exon 6 of 9	NP_001092099.1	Q13568-2
	IRF5	NM_001347928.2		c.575C>T	p.Pro192Leu	missense	Exon 6 of 9	NP_001334857.1	Q13568-2
	IRF5	NM_001364314.2		c.575C>T	p.Pro192Leu	missense	Exon 6 of 9	NP_001351243.1	Q13568-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF5	ENST00000357234.10	TSL:1 MANE Select	c.575C>T	p.Pro192Leu	missense	Exon 6 of 9	ENSP00000349770.5	Q13568-2
	IRF5	ENST00000402030.6	TSL:1	c.527C>T	p.Pro176Leu	missense	Exon 6 of 9	ENSP00000385352.2	Q13568-1
	IRF5	ENST00000477535.5	TSL:1	c.481+267C>T		intron	N/A	ENSP00000419950.1	Q13568-5

Frequencies

GnomAD3 genomes AF: 0.0000501 AC: 2 AN: 39902 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000170

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000574

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000173 AC: 4 AN: 231060 AF XY: 0.0000158

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000900

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000986

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000268 AC: 10 AN: 373312 Hom.: 0 Cov.: 0 AF XY: 0.0000216 AC XY: 4 AN XY: 185496

African (AFR) AF: 0.00 AC: 0 AN: 7538

American (AMR) AF: 0.000331 AC: 7 AN: 21130

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4344

East Asian (EAS) AF: 0.00 AC: 0 AN: 10626

South Asian (SAS) AF: 0.00 AC: 0 AN: 25524

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 14104

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1496

European-Non Finnish (NFE) AF: 0.0000110 AC: 3 AN: 273272

Other (OTH) AF: 0.00 AC: 0 AN: 15278

GnomAD4 genome AF: 0.0000501 AC: 2 AN: 39902 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 19940

African (AFR) AF: 0.00 AC: 0 AN: 9246

American (AMR) AF: 0.000170 AC: 1 AN: 5890

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 586

East Asian (EAS) AF: 0.00 AC: 0 AN: 1528

South Asian (SAS) AF: 0.00 AC: 0 AN: 1462

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2970

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 94

European-Non Finnish (NFE) AF: 0.0000574 AC: 1 AN: 17434

Other (OTH) AF: 0.00 AC: 0 AN: 542

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000271 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	15
DANN	Benign	0.74
DEOGEN2	Benign	0.099	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.082	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.055
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.20	N
REVEL	Uncertain	0.32
Sift	Benign	0.039	D
Sift4G	Benign	0.18	T
Polyphen		0.99	D
Vest4		0.29
MutPred		0.21		Loss of glycosylation at P176 (P = 0.0241)
MVP		0.85
MPC		0.051
ClinPred		0.078	T
Varity_R		0.11
gMVP		0.35
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs750603767; hg19: chr7-128587377;