GeneBe

rs553669430

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PM4_Supporting

The NM_022168.4(IFIH1):​c.1762_1764delAAA​(p.Lys588del) variant causes a conservative inframe deletion, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,786 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

IFIH1
NM_022168.4 conservative_inframe_deletion, splice_region

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.56

Publications

4 publications found
Variant links:
Genes affected
IFIH1 (HGNC:18873): (interferon induced with helicase C domain 1) IFIH1 encodes MDA5 which is an intracellular sensor of viral RNA that triggers the innate immune response. Sensing RNA length and secondary structure, MDA5 binds dsRNA oligonucleotides with a modified DExD/H-box helicase core and a C-terminal domain, thus leading to a proinflammatory response that includes interferons. It has been shown that Coronaviruses (CoVs) as well as various other virus families, are capable of evading the MDA5-dependent interferon response, thus impeding the activation of the innate immune response to infection. MDA5 has also been shown to play an important role in enhancing natural killer cell function in malaria infection. In addition to its protective role in antiviral responses, MDA5 has been implicated in autoimmune and autoinflammatory diseases such as type 1 diabetes, systemic lupus erythematosus, and Aicardi-Goutieres syndrome[provided by RefSeq, Jul 2020]
IFIH1 Gene-Disease associations (from GenCC):
  • Aicardi-Goutieres syndrome 7
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Illumina, Labcorp Genetics (formerly Invitae), G2P
  • Singleton-Merten syndrome 1
    Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
  • Aicardi-Goutieres syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • Singleton-Merten dysplasia
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • immunodeficiency 95
    Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_022168.4. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IFIH1NM_022168.4 linkc.1762_1764delAAA p.Lys588del conservative_inframe_deletion, splice_region_variant Exon 9 of 16 ENST00000649979.2 NP_071451.2 Q9BYX4-1
IFIH1XM_047445407.1 linkc.1045_1047delAAA p.Lys349del conservative_inframe_deletion, splice_region_variant Exon 8 of 15 XP_047301363.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IFIH1ENST00000649979.2 linkc.1762_1764delAAA p.Lys588del conservative_inframe_deletion, splice_region_variant Exon 9 of 16 NM_022168.4 ENSP00000497271.1 Q9BYX4-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00000427
AC:
1
AN:
234356
AF XY:
0.00000787
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000590
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.91e-7
AC:
1
AN:
1447786
Hom.:
0
AF XY:
0.00000139
AC XY:
1
AN XY:
720078
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:
0
AN:
32558
American (AMR)
AF:
0.00
AC:
0
AN:
41626
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25778
East Asian (EAS)
AF:
0.0000254
AC:
1
AN:
39322
South Asian (SAS)
AF:
0.00
AC:
0
AN:
83336
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53214
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
4996
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1107190
Other (OTH)
AF:
0.00
AC:
0
AN:
59766
⚠️ 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: 0.275
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
2.6

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs553669430; hg19: chr2-163134715; API