rs6748554

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

Scores

2
Splicing: ADA: 0.01695
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.476
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]

Genome browser will be placed here

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
IFIH1NM_022168.4 linkuse as main transcriptc.2454+6T>C splice_donor_region_variant, intron_variant ENST00000649979.2 NP_071451.2
IFIH1XM_047445407.1 linkuse as main transcriptc.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
IFIH1ENST00000649979.2 linkuse as main transcriptc.2454+6T>C splice_donor_region_variant, intron_variant NM_022168.4 ENSP00000497271 P1Q9BYX4-1

Frequencies

GnomAD3 genomes
AF:
0.0201
AC:
3054
AN:
152194
Hom.:
109
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0710
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00517
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000413
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.000162
Gnomad OTH
AF:
0.0100
GnomAD3 exomes
AF:
0.00561
AC:
1135
AN:
202294
Hom.:
50
AF XY:
0.00397
AC XY:
438
AN XY:
110362
show subpopulations
Gnomad AFR exome
AF:
0.0742
Gnomad AMR exome
AF:
0.00313
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000183
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000102
Gnomad OTH exome
AF:
0.00307
GnomAD4 exome
AF:
0.00185
AC:
2571
AN:
1387852
Hom.:
92
Cov.:
27
AF XY:
0.00159
AC XY:
1095
AN XY:
688628
show subpopulations
Gnomad4 AFR exome
AF:
0.0735
Gnomad4 AMR exome
AF:
0.00372
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000107
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000418
Gnomad4 OTH exome
AF:
0.00376
GnomAD4 genome
AF:
0.0201
AC:
3057
AN:
152312
Hom.:
109
Cov.:
32
AF XY:
0.0188
AC XY:
1402
AN XY:
74480
show subpopulations
Gnomad4 AFR
AF:
0.0708
Gnomad4 AMR
AF:
0.00517
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000162
Gnomad4 OTH
AF:
0.00992
Alfa
AF:
0.0110
Hom.:
20
Bravo
AF:
0.0231
Asia WGS
AF:
0.00202
AC:
7
AN:
3478

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 submitterclinical testingGeneDxJun 30, 2021- -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Aicardi-Goutieres syndrome 7;C4225427:Singleton-Merten syndrome 1 Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.68
CADD
Benign
8.4
DANN
Benign
0.60

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.017
dbscSNV1_RF
Benign
0.27
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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs6748554; hg19: chr2-163130299; API