rs6748554

chr2-162273789-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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: Splicing: ADA: 0.01695
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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]

ACMG classification

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	UniProt
IFIH1	NM_022168.4	c.2454+6T>C		splice_donor_region_variant, intron_variant		ENST00000649979.2
IFIH1	XM_047445407.1	c.1737+6T>C		splice_donor_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFIH1	ENST00000649979.2	c.2454+6T>C		splice_donor_region_variant, intron_variant			NM_022168.4	P1

Frequencies

GnomAD3 genomes AF: 0.0201 AC: 3054 AN: 152194 Hom.: 109 Cov.: 32

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

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

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

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 30, 2021

- -

Aicardi-Goutieres syndrome 7;C4225427:Singleton-Merten syndrome 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 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

Other links and lift over

dbSNP: rs6748554; hg19: chr2-163130299;