rs74162089

chr2-162267332-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_022168.4(IFIH1):c.2946C>T(p.Leu982=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,612,746 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (8 hom.)
• Consequence: IFIH1 NM_022168.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.209

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 2-162267332-G-A is Benign according to our data. Variant chr2-162267332-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 474957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-162267332-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.209 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFIH1	NM_022168.4	c.2946C>T	p.Leu982=	synonymous_variant	16/16	ENST00000649979.2
IFIH1	XM_047445407.1	c.2229C>T	p.Leu743=	synonymous_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFIH1	ENST00000649979.2	c.2946C>T	p.Leu982=	synonymous_variant	16/16		NM_022168.4	P1

Frequencies

GnomAD3 genomes AF: 0.00235 AC: 358 AN: 152104 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00509

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00125 AC: 311 AN: 249646 Hom.: 0 AF XY: 0.00127 AC XY: 171 AN XY: 134770

Gnomad AFR exome AF: 0.00444

Gnomad AMR exome AF: 0.00114

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000570

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00143

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00119 AC: 1737 AN: 1460524 Hom.: 8 Cov.: 31 AF XY: 0.00118 AC XY: 854 AN XY: 726398

Gnomad4 AFR exome AF: 0.00530

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.000842

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000654

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.00112

Gnomad4 OTH exome AF: 0.00179

GnomAD4 genome AF: 0.00235 AC: 358 AN: 152222 Hom.: 0 Cov.: 33 AF XY: 0.00239 AC XY: 178 AN XY: 74444

Gnomad4 AFR AF: 0.00505

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00143

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00199 Hom.: 0

Bravo AF: 0.00242

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00262

EpiControl AF: 0.00231

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aicardi-Goutieres syndrome 7;C4225427:Singleton-Merten syndrome 1;C5676929:Immunodeficiency 95 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 01, 2021

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2023

IFIH1: BP4, BP7 -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

IFIH1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 28, 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

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	3.1
Dann	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs74162089; hg19: chr2-163123842;