12-43771349-G-A

Variant names:

• chr12-43771349-G-A
• rs17851028
• NM_016123.4:c.291G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_016123.4(IRAK4):​c.291G>A​(p.Ala97Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000976 in 1,613,918 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A97A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00075 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (1 hom.)
• Consequence: IRAK4 NM_016123.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -1.01
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 12-43771349-G-A is Benign according to our data. Variant chr12-43771349-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 464934.
• BP7: Synonymous conserved (PhyloP=-1.01 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAK4	NM_016123.4	MANE Select	c.291G>A	p.Ala97Ala	synonymous	Exon 3 of 12	NP_057207.2
	IRAK4	NM_001114182.3		c.291G>A	p.Ala97Ala	synonymous	Exon 4 of 13	NP_001107654.1
	IRAK4	NM_001351345.2		c.291G>A	p.Ala97Ala	synonymous	Exon 4 of 13	NP_001338274.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAK4	ENST00000613694.5	TSL:1 MANE Select	c.291G>A	p.Ala97Ala	synonymous	Exon 3 of 12	ENSP00000479889.3
	IRAK4	ENST00000551736.5	TSL:1	c.291G>A	p.Ala97Ala	synonymous	Exon 4 of 13	ENSP00000446490.1
	IRAK4	ENST00000547101.5	TSL:1	n.*193G>A		non_coding_transcript_exon	Exon 4 of 13	ENSP00000449317.1

Frequencies

GnomAD3 genomes AF: 0.000749 AC: 114 AN: 152102 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000662

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000812 AC: 204 AN: 251324 AF XY: 0.000773

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00268

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000832

Gnomad NFE exome AF: 0.00113

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000999 AC: 1461 AN: 1461816 Hom.: 1 Cov.: 32 AF XY: 0.00102 AC XY: 741 AN XY: 727214

African (AFR) AF: 0.000179 AC: 6 AN: 33478

American (AMR) AF: 0.000492 AC: 22 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00283 AC: 74 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000394 AC: 34 AN: 86258

European-Finnish (FIN) AF: 0.00109 AC: 58 AN: 53410

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00108 AC: 1204 AN: 1111976

Other (OTH) AF: 0.00101 AC: 61 AN: 60392

GnomAD4 genome AF: 0.000749 AC: 114 AN: 152102 Hom.: 0 Cov.: 32 AF XY: 0.000579 AC XY: 43 AN XY: 74298

African (AFR) AF: 0.000314 AC: 13 AN: 41422

American (AMR) AF: 0.000917 AC: 14 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.000662 AC: 7 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00103 AC: 70 AN: 68020

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.000823 Hom.: 0

Bravo AF: 0.000835

EpiCase AF: 0.000600

EpiControl AF: 0.00107

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Immunodeficiency 67 (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	5.2
DANN	Benign	0.55
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism

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: rs17851028; hg19: chr12-44165152;