rs976991963

Variant names:

• chr12-66189430-T-C
• rs976991963
• NM_007199.3:c.131T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PP3_Strong BS2

The NM_007199.3(IRAK3):​c.131T>C​(p.Leu44Pro) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000238 in 1,300,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: IRAK3 NM_007199.3 missense, splice_region
• Scores: Splicing: ADA: 0.004310
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.71
• Publications: 1 publications found

Genes affected

IRAK3 (HGNC:17020): (interleukin 1 receptor associated kinase 3) This gene encodes a member of the interleukin-1 receptor-associated kinase protein family. Members of this family are essential components of the Toll/IL-R immune signal transduction pathways. This protein is primarily expressed in monocytes and macrophages and functions as a negative regulator of Toll-like receptor signaling. Mutations in this gene are associated with a susceptibility to asthma. Alternate splicing results in multiple transcript variants. [provided by RefSeq, May 2010]

IRAK3 Gene-Disease associations (from GenCC):

• asthma-related traits, susceptibility to, 5

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958
• BS2: High AC in GnomAd4 at 9 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007199.3. 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
	IRAK3	NM_007199.3	MANE Select	c.131T>C	p.Leu44Pro	missense splice_region	Exon 1 of 12	NP_009130.2	Q9Y616-1
	IRAK3	NM_001142523.2		c.131T>C	p.Leu44Pro	missense splice_region	Exon 1 of 11	NP_001135995.1	Q9Y616-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IRAK3	ENST00000261233.9	TSL:1 MANE Select	c.131T>C	p.Leu44Pro	missense splice_region	Exon 1 of 12	ENSP00000261233.4	Q9Y616-1
	IRAK3	ENST00000545837.1	TSL:1	c.131T>C	p.Leu44Pro	missense splice_region	Exon 1 of 2	ENSP00000441321.1	F5GYN6
	IRAK3	ENST00000854785.1		c.131T>C	p.Leu44Pro	missense splice_region	Exon 1 of 12	ENSP00000524844.1

Frequencies

GnomAD3 genomes AF: 0.0000595 AC: 9 AN: 151318 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.000133

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000191 AC: 22 AN: 1149636 Hom.: 0 Cov.: 30 AF XY: 0.0000198 AC XY: 11 AN XY: 554696

African (AFR) AF: 0.0000856 AC: 2 AN: 23360

American (AMR) AF: 0.00 AC: 0 AN: 11540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16186

East Asian (EAS) AF: 0.00 AC: 0 AN: 25240

South Asian (SAS) AF: 0.00 AC: 0 AN: 44184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25228

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3122

European-Non Finnish (NFE) AF: 0.0000209 AC: 20 AN: 954740

Other (OTH) AF: 0.00 AC: 0 AN: 46036

GnomAD4 genome AF: 0.0000595 AC: 9 AN: 151318 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 73880

African (AFR) AF: 0.00 AC: 0 AN: 41300

American (AMR) AF: 0.00 AC: 0 AN: 15178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10332

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

European-Non Finnish (NFE) AF: 0.000133 AC: 9 AN: 67776

Other (OTH) AF: 0.00 AC: 0 AN: 2074

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000604

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	29
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.67	D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.62	T
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	-0.028	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.7
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.82		Gain of catalytic residue at L39 (P = 0)
MVP		0.91
MPC		0.20
ClinPred		0.94	D
GERP RS		3.4
PromoterAI		-0.082	Neutral
Varity_R		0.81
gMVP		0.75
Mutation Taster		=39/61	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0043
dbscSNV1_RF	Benign	0.11
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: rs976991963; hg19: chr12-66583210;