NM_001098629.3:c.447G>T

Variant names:

• chr7-128946562-G-T
• NM_001098629.3:c.447G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001098629.3(IRF5):​c.447G>T​(p.Glu149Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,439,242 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IRF5 NM_001098629.3 missense, splice_region
• Scores: Splicing: ADA: 0.9936
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0540

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF5	NM_001098629.3	c.447G>T	p.Glu149Asp	missense_variant, splice_region_variant	Exon 4 of 9	ENST00000357234.10	NP_001092099.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF5	ENST00000357234.10	c.447G>T	p.Glu149Asp	missense_variant, splice_region_variant	Exon 4 of 9	1	NM_001098629.3	ENSP00000349770.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1439242 Hom.: 0 Cov.: 26 AF XY: 0.00000140 AC XY: 1 AN XY: 715562

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: 0.0000195

Gnomad4 NFE exome AF: 9.11e-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	0.16
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	.;.;.;.;T;T;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.42	.;T;T;T;.;T;.
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.13	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	1.2	L;.;L;L;L;L;L
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.080	N;.;N;N;N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.18	T;.;T;T;T;T;T
Sift4G	Benign	0.58	T;T;T;T;T;T;T
Polyphen		0.0010	B;.;B;.;B;B;B
Vest4		0.18, 0.19, 0.21, 0.18, 0.18
MutPred		0.19		Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);
MVP		0.91
MPC		0.010
ClinPred		0.10	T
GERP RS		3.6
Varity_R		0.058
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.72
SpliceAI score (max)		0.080		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: chr7-128586616;