12-66189300-A-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PVS1_Supporting BP6_Moderate BS2

The NM_007199.3(IRAK3):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000211 in 1,536,240 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00040 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00019 (2 hom.)
• Consequence: IRAK3 NM_007199.3 start_lost
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• 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: Likely_benign. The variant received -5 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.
• BP6: Variant 12-66189300-A-G is Benign according to our data. Variant chr12-66189300-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 736195.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 61 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IRAK3	NM_007199.3	c.1A>G	p.Met1?	start_lost	Exon 1 of 12	ENST00000261233.9	NP_009130.2
IRAK3	NM_001142523.2	c.1A>G	p.Met1?	start_lost	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>G	p.Met1?	start_lost	Exon 1 of 12	1	NM_007199.3	ENSP00000261233.4
IRAK3	ENST00000545837.1	c.1A>G	p.Met1?	start_lost	Exon 1 of 2	1		ENSP00000441321.1
IRAK3	ENST00000457197.2	c.1A>G	p.Met1?	start_lost	Exon 1 of 11	2		ENSP00000409852.2

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152194 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00349

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000204 AC: 27 AN: 132448 AF XY: 0.000206

Gnomad AFR exome AF: 0.000155

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00346

Gnomad NFE exome AF: 0.000140

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000190 AC: 263 AN: 1383928 Hom.: 2 Cov.: 31 AF XY: 0.000184 AC XY: 126 AN XY: 683186

African (AFR) AF: 0.0000315 AC: 1 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: 0.0000278 AC: 1 AN: 36034

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

European-Finnish (FIN) AF: 0.00417 AC: 140 AN: 33598

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

European-Non Finnish (NFE) AF: 0.0000954 AC: 103 AN: 1079698

Other (OTH) AF: 0.000312 AC: 18 AN: 57764

GnomAD4 genome AF: 0.000400 AC: 61 AN: 152312 Hom.: 1 Cov.: 33 AF XY: 0.000497 AC XY: 37 AN XY: 74490

African (AFR) AF: 0.000168 AC: 7 AN: 41582

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00349 AC: 37 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000794 Hom.: 0

Bravo AF: 0.0000831

ExAC AF: 0.000345 AC: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 30, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Uncertain	0.050
CADD	Benign	20
DANN	Benign	0.89
DEOGEN2	Benign	0.11	T;.;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Benign	-0.85	T
PhyloP100		1.8
PROVEAN	Benign	-1.8	N;N;N
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.12	B;B;B
Vest4		0.64
MutPred		0.98		Gain of catalytic residue at C5 (P = 0.0011);Gain of catalytic residue at C5 (P = 0.0011);Gain of catalytic residue at C5 (P = 0.0011);
MVP		0.83
ClinPred		0.40	T
GERP RS		3.3
PromoterAI		-0.40	Neutral
Varity_R		0.95
gMVP		0.32
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;