7-128945875-G-C

Variant names:

• chr7-128945875-G-C
• NM_001098629.3:c.226G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001098629.3(IRF5):​c.226G>C​(p.Glu76Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: IRF5 NM_001098629.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.60

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.746

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF5	NM_001098629.3	c.226G>C	p.Glu76Gln	missense_variant	Exon 3 of 9	ENST00000357234.10	NP_001092099.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF5	ENST00000357234.10	c.226G>C	p.Glu76Gln	missense_variant	Exon 3 of 9	1	NM_001098629.3	ENSP00000349770.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460438 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726582

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	.;.;.;.;D;D;D;D;D;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;D;D;D;D;D;.;D;.;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M;.;M;M;.;.;M;M;M;M
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.1	N;.;N;D;N;N;D;D;D;.
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0010	D;.;D;D;D;T;D;D;D;.
Sift4G	Uncertain	0.029	D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;D;.;.;.;D;D;D;.
Vest4		0.51, 0.40, 0.45, 0.39, 0.39, 0.39, 0.53
MutPred		0.42		Loss of disorder (P = 0.1093);Loss of disorder (P = 0.1093);Loss of disorder (P = 0.1093);Loss of disorder (P = 0.1093);Loss of disorder (P = 0.1093);Loss of disorder (P = 0.1093);Loss of disorder (P = 0.1093);Loss of disorder (P = 0.1093);Loss of disorder (P = 0.1093);Loss of disorder (P = 0.1093);
MVP		0.94
MPC		1.6
ClinPred		0.97	D
GERP RS		4.8
Varity_R		0.37
gMVP		0.66

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-128585929;