chr11-613444-G-T

Variant names:

• chr11-613444-G-T
• rs751249139
• NM_001572.5:c.999C>A

Variant summary

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

The NM_001572.5(IRF7):​c.999C>A​(p.Ser333Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,401,684 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S333N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: IRF7 NM_001572.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.57
• Publications: 0 publications found

Genes affected

IRF7 (HGNC:6122): (interferon regulatory factor 7) This gene encodes interferon regulatory factor 7, a member of the interferon regulatory transcription factor (IRF) family. It has been shown to play a role in the transcriptional activation of virus-inducible cellular genes, including interferon beta chain genes. Inducible expression of IRF7 is largely restricted to lymphoid tissue. The encoded protein plays an important role in the innate immune response against DNA and RNA viruses. [provided by RefSeq, Jul 2021]

IRF7 Gene-Disease associations (from GenCC):

• immunodeficiency 39

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001572.5. 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
	IRF7	NM_001572.5	MANE Select	c.999C>A	p.Ser333Arg	missense	Exon 9 of 11	NP_001563.2
	IRF7	NM_004031.4		c.1038C>A	p.Ser346Arg	missense	Exon 8 of 10	NP_004022.2	Q92985-4
	IRF7	NM_001440440.1		c.1035C>A	p.Ser345Arg	missense	Exon 8 of 10	NP_001427369.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF7	ENST00000525445.6	TSL:5 MANE Select	c.999C>A	p.Ser333Arg	missense	Exon 9 of 11	ENSP00000434009.2	Q92985-1
	IRF7	ENST00000397566.5	TSL:1	c.1038C>A	p.Ser346Arg	missense	Exon 7 of 9	ENSP00000380697.1	Q92985-4
	IRF7	ENST00000397570.5	TSL:1	c.951C>A	p.Ser317Arg	missense	Exon 6 of 8	ENSP00000380700.2	M9RSF4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1401684 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 691520

African (AFR) AF: 0.00 AC: 0 AN: 31730

American (AMR) AF: 0.00 AC: 0 AN: 35922

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22142

East Asian (EAS) AF: 0.00 AC: 0 AN: 39142

South Asian (SAS) AF: 0.00 AC: 0 AN: 77578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49914

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5506

European-Non Finnish (NFE) AF: 9.24e-7 AC: 1 AN: 1081968

Other (OTH) AF: 0.00 AC: 0 AN: 57782

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Benign	0.085
Eigen_PC	Benign	-0.055
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.066	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Benign	-0.72	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		1.6
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.25
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.32
MutPred		0.49		Loss of glycosylation at S333 (P = 0.0299)
MVP		0.77
MPC		0.55
ClinPred		0.99	D
GERP RS		2.4
Varity_R		0.72
gMVP		0.68
Mutation Taster		=46/54	disease causing

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: rs751249139; hg19: chr11-613444;