7-128945890-G-T

Variant names:

• chr7-128945890-G-T
• NM_001098629.3:c.241G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001098629.3(IRF5):​c.241G>T​(p.Ala81Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IRF5 NM_001098629.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.66
• Publications: 0 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: Uncertain_significance. The variant received 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.241G>T	p.Ala81Ser	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.241G>T	p.Ala81Ser	missense_variant	Exon 3 of 9	1	NM_001098629.3	ENSP00000349770.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.241G>T (p.A81S) alteration is located in exon 3 (coding exon 2) of the IRF5 gene. This alteration results from a G to T substitution at nucleotide position 241, causing the alanine (A) at amino acid position 81 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	.;.;.;.;T;T;D;D;D;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.90	.;D;D;D;D;T;.;D;.;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.54	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Benign	1.4	L;.;L;L;.;.;L;L;L;L
PhyloP100		6.7
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.1	N;.;N;N;N;N;N;N;N;.
REVEL	Uncertain	0.54
Sift	Benign	0.078	T;.;D;T;T;T;D;D;D;.
Sift4G	Benign	0.25	T;T;D;T;T;T;D;D;D;T
Polyphen		1.0	D;.;D;.;.;.;D;D;D;.
Vest4		0.18, 0.23, 0.23, 0.24, 0.24, 0.37
MutPred		0.49		Gain of phosphorylation at A81 (P = 0.0771);Gain of phosphorylation at A81 (P = 0.0771);Gain of phosphorylation at A81 (P = 0.0771);Gain of phosphorylation at A81 (P = 0.0771);Gain of phosphorylation at A81 (P = 0.0771);Gain of phosphorylation at A81 (P = 0.0771);Gain of phosphorylation at A81 (P = 0.0771);Gain of phosphorylation at A81 (P = 0.0771);Gain of phosphorylation at A81 (P = 0.0771);Gain of phosphorylation at A81 (P = 0.0771);
MVP		0.92
MPC		1.6
ClinPred		0.92	D
GERP RS		5.1
Varity_R		0.11
gMVP		0.24
Mutation Taster		=55/45	polymorphism

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

hg19: chr7-128585944;