2-162278205-CTTT-CTTTT

Position:

• chr2-162278205-CTTT-CTTTT

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 8P and 5B. PVS1 BP6 BS2

The NM_022168.4(IFIH1):​c.1764dupA​(p.Ala589fs) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000527 in 1,599,554 control chromosomes in the GnomAD database, including 3 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0018 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (0 hom.)
• Consequence: IFIH1 NM_022168.4 frameshift, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 2.56

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 2-162278205-C-CT is Benign according to our data. Variant chr2-162278205-C-CT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 541791.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFIH1	NM_022168.4	c.1764dupA	p.Ala589fs	frameshift_variant, splice_region_variant	9/16	ENST00000649979.2	NP_071451.2
IFIH1	XM_047445407.1	c.1047dupA	p.Ala350fs	frameshift_variant, splice_region_variant	8/15		XP_047301363.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFIH1	ENST00000649979.2	c.1764dupA	p.Ala589fs	frameshift_variant, splice_region_variant	9/16		NM_022168.4	ENSP00000497271.1

Frequencies

GnomAD3 genomes AF: 0.00182 AC: 277 AN: 151906 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00593

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000606 AC: 142 AN: 234356 Hom.: 1 AF XY: 0.000480 AC XY: 61 AN XY: 127092

Gnomad AFR exome AF: 0.00661

Gnomad AMR exome AF: 0.000269

Gnomad ASJ exome AF: 0.000105

Gnomad EAS exome AF: 0.000118

Gnomad SAS exome AF: 0.0000728

Gnomad FIN exome AF: 0.000141

Gnomad NFE exome AF: 0.000222

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000391 AC: 566 AN: 1447530 Hom.: 0 Cov.: 29 AF XY: 0.000361 AC XY: 260 AN XY: 719968

Gnomad4 AFR exome AF: 0.00562

Gnomad4 AMR exome AF: 0.000264

Gnomad4 ASJ exome AF: 0.0000388

Gnomad4 EAS exome AF: 0.00234

Gnomad4 SAS exome AF: 0.0000720

Gnomad4 FIN exome AF: 0.000263

Gnomad4 NFE exome AF: 0.000201

Gnomad4 OTH exome AF: 0.000602

GnomAD4 genome AF: 0.00182 AC: 277 AN: 152024 Hom.: 3 Cov.: 32 AF XY: 0.00166 AC XY: 123 AN XY: 74320

Gnomad4 AFR AF: 0.00591

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000948

Bravo AF: 0.00213

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 24, 2019

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

- -

IFIH1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 29, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs553669430; hg19: chr2-163134715;