rs587777446

Positions:

• chr2-162273913-C-A
• chr2-162273913-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_022168.4(IFIH1):​c.2336G>T​(p.Arg779Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R779C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IFIH1 NM_022168.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.15

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 Pathogenic. Variant got 18 ACMG points.

• PM1: In a domain Helicase C-terminal (size 182) in uniprot entity IFIH1_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_022168.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-162273914-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant 2-162273913-C-A is Pathogenic according to our data. Variant chr2-162273913-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 812532.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFIH1	NM_022168.4	c.2336G>T	p.Arg779Leu	missense_variant	12/16	ENST00000649979.2	NP_071451.2
IFIH1	XM_047445407.1	c.1619G>T	p.Arg540Leu	missense_variant	11/15		XP_047301363.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFIH1	ENST00000649979.2	c.2336G>T	p.Arg779Leu	missense_variant	12/16		NM_022168.4	ENSP00000497271	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aicardi-Goutieres syndrome 7 Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Neurogenetics and Neuroinflammation, Institut Imagine	Jun 11, 2019	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Service de Biochimie Médicale et Biologie Moléculaire, CHU Clermont-Ferrand	Feb 03, 2020	Variation p.(Arg799Leu) is absent from gnomAD. Two substitutions affecting the same amino-acid change is described with functional studies (Rice , 2014) indicating a "gain of function". There are 11 pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, PrimateAI, REVEL and SIFT vs no benign predictions. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 10, 2023

This missense change has been observed in individual(s) with Aicardi–Goutières syndrome (PMID: 31898846). In at least one individual the variant was observed to be de novo. This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 779 of the IFIH1 protein (p.Arg779Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in at least one individual who was not affected with IFIH1-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 812532). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt IFIH1 protein function. This variant disrupts the p.Arg779 amino acid residue in IFIH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31898846; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Singleton-Merten syndrome 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

May 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;D;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Uncertain	2.5	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.2	.;D;.
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0040	.;D;.
Sift4G	Uncertain	0.0050	.;D;.
Polyphen		1.0	D;D;.
Vest4		0.91
MutPred		0.87		Loss of MoRF binding (P = 0.0375);Loss of MoRF binding (P = 0.0375);.;
MVP		0.91
MPC		0.21
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.76
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs587777446; hg19: chr2-163130423;