7-128942125-T-G

Variant names:

• chr7-128942125-T-G
• rs2128959402
• NM_001098629.3:c.44T>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001098629.3(IRF5):​c.44T>G​(p.Val15Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V15M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: IRF5 NM_001098629.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.55
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRF5	NM_001098629.3	c.44T>G	p.Val15Gly	missense_variant	Exon 2 of 9	ENST00000357234.10	NP_001092099.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRF5	ENST00000357234.10	c.44T>G	p.Val15Gly	missense_variant	Exon 2 of 9	1	NM_001098629.3	ENSP00000349770.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 05, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.44T>G (p.V15G) alteration is located in exon 2 (coding exon 1) of the IRF5 gene. This alteration results from a T to G substitution at nucleotide position 44, causing the valine (V) at amino acid position 15 to be replaced by a glycine (G). 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	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	.;.;.;.;T;T;T;T;T;T;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	.;D;T;D;D;D;.;D;D;.;D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M;.;M;M;.;.;M;M;.;M;M
PhyloP100		5.6
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-4.8	D;.;N;D;D;D;N;N;D;N;.
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	D;.;D;D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.79	P;.;P;.;.;.;D;D;.;D;.
Vest4		0.51, 0.48, 0.48, 0.46, 0.46, 0.51
MutPred		0.79		Loss of stability (P = 0.0023);Loss of stability (P = 0.0023);Loss of stability (P = 0.0023);Loss of stability (P = 0.0023);Loss of stability (P = 0.0023);Loss of stability (P = 0.0023);Loss of stability (P = 0.0023);Loss of stability (P = 0.0023);Loss of stability (P = 0.0023);Loss of stability (P = 0.0023);Loss of stability (P = 0.0023);
MVP		0.98
MPC		1.7
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.52
gMVP		0.67
Mutation Taster		=48/52	disease causing

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: rs2128959402; hg19: chr7-128582179;