chr12-66189300-A-C

Variant names:

• chr12-66189300-A-C
• rs760304982
• NM_007199.3:c.1A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_007199.3(IRAK3):​c.1A>C​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,383,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: IRAK3 NM_007199.3 initiator_codon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.80
• Publications: 0 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 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 93 codons. Genomic position: 66203854. Lost 0.155 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRAK3	NM_007199.3	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 12	ENST00000261233.9	NP_009130.2
IRAK3	NM_001142523.2	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 11		NP_001135995.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IRAK3	ENST00000261233.9	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 12	1	NM_007199.3	ENSP00000261233.4
IRAK3	ENST00000545837.1	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 2	1		ENSP00000441321.1
IRAK3	ENST00000457197.2	c.1A>C	p.Met1?	initiator_codon_variant	Exon 1 of 11	2		ENSP00000409852.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1383928 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 683186

African (AFR) AF: 0.00 AC: 0 AN: 31698

American (AMR) AF: 0.00 AC: 0 AN: 35894

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25090

East Asian (EAS) AF: 0.00 AC: 0 AN: 36034

South Asian (SAS) AF: 0.00 AC: 0 AN: 79410

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4742

European-Non Finnish (NFE) AF: 9.26e-7 AC: 1 AN: 1079698

Other (OTH) AF: 0.00 AC: 0 AN: 57764

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	18
DANN	Benign	0.79
DEOGEN2	Benign	0.096	T;.;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Benign	-0.91	T
PhyloP100		1.8
PROVEAN	Benign	-1.3	N;N;N
REVEL	Uncertain	0.38
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.055	B;B;B
Vest4		0.53
MutPred		0.98		Gain of catalytic residue at N4 (P = 6e-04);Gain of catalytic residue at N4 (P = 6e-04);Gain of catalytic residue at N4 (P = 6e-04);
MVP		0.85
ClinPred		0.99	D
GERP RS		3.3
PromoterAI		-0.38	Neutral
Varity_R		0.97
gMVP		0.25
Mutation Taster		=21/179	disease causing

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: rs760304982; hg19: chr12-66583080;