chr12-43773045-A-C

Variant names:

• chr12-43773045-A-C
• rs1555168129
• NM_016123.4:c.624A>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_016123.4(IRAK4):​c.624A>C​(p.Thr208Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: IRAK4 NM_016123.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.11
• Publications: 0 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07957685).
• BP6: Variant 12-43773045-A-C is Benign according to our data. Variant chr12-43773045-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 533527.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.12 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.624A>C	p.Thr208Thr	synonymous	Exon 5 of 12	NP_057207.2
	IRAK4	NM_001114182.3		c.624A>C	p.Thr208Thr	synonymous	Exon 6 of 13	NP_001107654.1
	IRAK4	NM_001351345.2		c.624A>C	p.Thr208Thr	synonymous	Exon 6 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.624A>C	p.Thr208Thr	synonymous	Exon 5 of 12	ENSP00000479889.3
	IRAK4	ENST00000551736.5	TSL:1	c.624A>C	p.Thr208Thr	synonymous	Exon 6 of 13	ENSP00000446490.1
	IRAK4	ENST00000547101.5	TSL:1	n.*526A>C		non_coding_transcript_exon	Exon 6 of 13	ENSP00000449317.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Immunodeficiency 67 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.3
DANN	Benign	0.36
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.25	T
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.1
Vest4		0.25
MVP		0.36
ClinPred		0.041	T
GERP RS		-2.7

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: rs1555168129; hg19: chr12-44166848;