12-43760887-G-T

Variant names:

• chr12-43760887-G-T
• rs4251431
• NM_016123.4:c.-10+1871G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016123.4(IRAK4):​c.-10+1871G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 151,158 control chromosomes in the GnomAD database, including 1,554 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.13 (1554 hom., cov: 32)
  • Exomes 𝑓: 0.13 (0 hom.)
• Consequence: IRAK4 NM_016123.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.589
• Publications: 15 publications found

Genes affected

IRAK4 (HGNC:17967): (interleukin 1 receptor associated kinase 4) This gene encodes a kinase that activates NF-kappaB in both the Toll-like receptor (TLR) and T-cell receptor (TCR) signaling pathways. The protein is essential for most innate immune responses. Mutations in this gene result in IRAK4 deficiency and recurrent invasive pneumococcal disease. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

IRAK4 Gene-Disease associations (from GenCC):

• immunodeficiency 67

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016123.4. 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
	IRAK4	NM_016123.4	MANE Select	c.-10+1871G>T		intron	N/A	NP_057207.2	Q9NWZ3-1
	IRAK4	NM_001114182.3		c.-57-38G>T		intron	N/A	NP_001107654.1	Q9NWZ3-1
	IRAK4	NM_001351345.2		c.-57-38G>T		intron	N/A	NP_001338274.1	Q69FE3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAK4	ENST00000613694.5	TSL:1 MANE Select	c.-10+1871G>T		intron	N/A	ENSP00000479889.3	Q9NWZ3-1
	IRAK4	ENST00000551736.5	TSL:1	c.-57-38G>T		intron	N/A	ENSP00000446490.1	Q9NWZ3-1
	IRAK4	ENST00000547101.5	TSL:1	n.-10+1871G>T		intron	N/A	ENSP00000449317.1	F8VW24

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19771 AN: 151038 Hom.: 1544 Cov.: 32

Gnomad AFR AF: 0.218

Gnomad AMI AF: 0.0407

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.117

Gnomad FIN AF: 0.0582

Gnomad MID AF: 0.175

Gnomad NFE AF: 0.0915

Gnomad OTH AF: 0.141

GnomAD4 exome AF: 0.125 AC: 1 AN: 8 Hom.: 0 Cov.: 0 AF XY: 0.125 AC XY: 1 AN XY: 8

African (AFR) AF: 0.500 AC: 1 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 4

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.131 AC: 19800 AN: 151150 Hom.: 1554 Cov.: 32 AF XY: 0.129 AC XY: 9502 AN XY: 73826

African (AFR) AF: 0.218 AC: 8978 AN: 41108

American (AMR) AF: 0.132 AC: 2013 AN: 15206

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 533 AN: 3454

East Asian (EAS) AF: 0.105 AC: 537 AN: 5136

South Asian (SAS) AF: 0.117 AC: 560 AN: 4798

European-Finnish (FIN) AF: 0.0582 AC: 605 AN: 10402

Middle Eastern (MID) AF: 0.178 AC: 52 AN: 292

European-Non Finnish (NFE) AF: 0.0914 AC: 6193 AN: 67742

Other (OTH) AF: 0.139 AC: 292 AN: 2102

Alfa AF: 0.101 Hom.: 2036

Bravo AF: 0.140

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.36
DANN	Benign	0.083
PhyloP100		-0.59
Mutation Taster		=100/0	polymorphism (auto)

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: rs4251431; hg19: chr12-44154690;