dbSNP rs148053167: IRAK1BP1:p.Ala106Glu (chr6-78885379-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001010844.4(IRAK1BP1):c.317C>A(p.Ala106Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,413,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A106V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

IRAK1BP1
NM_001010844.4 missense, splice_region

Scores

Splicing: ADA: 0.0007129

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.14

Publications

5 publications found

Variant links:

Genes affected

IRAK1BP1 (HGNC:17368): (interleukin 1 receptor associated kinase 1 binding protein 1) Predicted to be involved in I-kappaB kinase/NF-kappaB signaling. Predicted to be located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

IRAK1BP1 links:

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ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.074003786).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001010844.4. 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
	IRAK1BP1	NM_001010844.4	MANE Select	c.317C>A	p.Ala106Glu	missense splice_region	Exon 2 of 4	NP_001010844.1	Q5VVH5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IRAK1BP1	ENST00000369940.7	TSL:1 MANE Select	c.317C>A	p.Ala106Glu	missense splice_region	Exon 2 of 4	ENSP00000358956.1	Q5VVH5
IRAK1BP1	ENST00000606868.5	TSL:1	n.287C>A		splice_region non_coding_transcript_exon	Exon 2 of 5	ENSP00000475570.1	U3KQ57
IRAK1BP1	ENST00000607739.1	TSL:2	c.56C>A	p.Ala19Glu	missense splice_region	Exon 2 of 5	ENSP00000475503.1	U3KQ34

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000418

AC:

AN:

239122

AF XY:

0.00000771

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.07e-7

AC:

AN:

1413508

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

705762

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32198

American (AMR)

AF:

0.00

AC:

AN:

40950

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25732

East Asian (EAS)

AF:

0.00

AC:

AN:

38874

South Asian (SAS)

AF:

0.0000121

AC:

AN:

82834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53314

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5670

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1075258

Other (OTH)

AF:

0.00

AC:

AN:

58678

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.33

DEOGEN2

Benign

0.0058

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.10

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.52

M_CAP

Benign

0.0032

MetaRNN

Benign

0.036

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.69

PhyloP100

1.1

PrimateAI

Benign

0.31

PROVEAN

Benign

2.0

REVEL

Benign

0.097

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0070

Vest4

0.14

MutPred

0.37

Gain of disorder (P = 0.0317)

MVP

0.28

MPC

0.071

ClinPred

0.24

GERP RS

4.3

Varity_R

0.056

gMVP

0.20

Mutation Taster

=80/20

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00071

dbscSNV1_RF

Benign

0.032

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over