rs6748554
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Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_022168.4(IFIH1):c.2454+6T>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00365 in 1,540,164 control chromosomes in the GnomAD database, including 201 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.020 ( 109 hom., cov: 32)
Exomes 𝑓: 0.0019 ( 92 hom. )
Consequence
IFIH1
NM_022168.4 splice_donor_region, intron
NM_022168.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.01695
2
Clinical Significance
Conservation
PhyloP100: 0.476
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -20 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.68).
BP6
Variant 2-162273789-A-G is Benign according to our data. Variant chr2-162273789-A-G is described in ClinVar as [Benign]. Clinvar id is 474948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0687 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
IFIH1 | NM_022168.4 | c.2454+6T>C | splice_donor_region_variant, intron_variant | ENST00000649979.2 | NP_071451.2 | |||
IFIH1 | XM_047445407.1 | c.1737+6T>C | splice_donor_region_variant, intron_variant | XP_047301363.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
IFIH1 | ENST00000649979.2 | c.2454+6T>C | splice_donor_region_variant, intron_variant | NM_022168.4 | ENSP00000497271 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0201 AC: 3054AN: 152194Hom.: 109 Cov.: 32
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GnomAD3 exomes AF: 0.00561 AC: 1135AN: 202294Hom.: 50 AF XY: 0.00397 AC XY: 438AN XY: 110362
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GnomAD4 exome AF: 0.00185 AC: 2571AN: 1387852Hom.: 92 Cov.: 27 AF XY: 0.00159 AC XY: 1095AN XY: 688628
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GnomAD4 genome AF: 0.0201 AC: 3057AN: 152312Hom.: 109 Cov.: 32 AF XY: 0.0188 AC XY: 1402AN XY: 74480
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ClinVar
Significance: Benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 30, 2021 | - - |
Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Aicardi-Goutieres syndrome 7;C4225427:Singleton-Merten syndrome 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at