chr6-393191-C-T

Variant names:

• chr6-393191-C-T
• rs989430246
• NM_002460.4:c.39C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_002460.4(IRF4):​c.39C>T​(p.Gly13Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000129 in 1,555,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: IRF4 NM_002460.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.417
• Publications: 0 publications found

Genes affected

IRF4 (HGNC:6119): (interferon regulatory factor 4) The protein encoded by this gene belongs to the IRF (interferon regulatory factor) family of transcription factors, characterized by an unique tryptophan pentad repeat DNA-binding domain. The IRFs are important in the regulation of interferons in response to infection by virus, and in the regulation of interferon-inducible genes. This family member is lymphocyte specific and negatively regulates Toll-like-receptor (TLR) signaling that is central to the activation of innate and adaptive immune systems. A chromosomal translocation involving this gene and the IgH locus, t(6;14)(p25;q32), may be a cause of multiple myeloma. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2010]

IRF4 Gene-Disease associations (from GenCC):

• combined immunodeficiency

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 6-393191-C-T is Benign according to our data. Variant chr6-393191-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2790560.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.417 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002460.4. 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
	IRF4	NM_002460.4	MANE Select	c.39C>T	p.Gly13Gly	synonymous	Exon 2 of 9	NP_002451.2	Q15306-1
	IRF4	NM_001195286.2		c.39C>T	p.Gly13Gly	synonymous	Exon 2 of 9	NP_001182215.1	Q15306-2
	IRF4	NR_046000.3		n.152C>T		non_coding_transcript_exon	Exon 2 of 10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRF4	ENST00000380956.9	TSL:1 MANE Select	c.39C>T	p.Gly13Gly	synonymous	Exon 2 of 9	ENSP00000370343.4	Q15306-1
	IRF4	ENST00000866554.1		c.39C>T	p.Gly13Gly	synonymous	Exon 2 of 9	ENSP00000536613.1
	IRF4	ENST00000696871.1		c.39C>T	p.Gly13Gly	synonymous	Exon 2 of 9	ENSP00000512940.1	Q15306-2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151880 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1403406 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 692766

African (AFR) AF: 0.00 AC: 0 AN: 32008

American (AMR) AF: 0.00 AC: 0 AN: 36062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25186

East Asian (EAS) AF: 0.00 AC: 0 AN: 36324

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79556

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49076

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5628

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1081400

Other (OTH) AF: 0.00 AC: 0 AN: 58166

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151880 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74202

African (AFR) AF: 0.0000242 AC: 1 AN: 41342

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67942

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	15
DANN	Uncertain	0.97
PhyloP100		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs989430246; hg19: chr6-393191;