2-162273913-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>A(p.Arg779His) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,455,194 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: IFIH1 NM_022168.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• 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 hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 7 uncertain 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 ClinVar as [Pathogenic]. Clinvar id is 137624.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.951
• PP5: Variant 2-162273913-C-T is Pathogenic according to our data. Variant chr2-162273913-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 137622.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-162273913-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFIH1	NM_022168.4	c.2336G>A	p.Arg779His	missense_variant	12/16	ENST00000649979.2
IFIH1	XM_047445407.1	c.1619G>A	p.Arg540His	missense_variant	11/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFIH1	ENST00000649979.2	c.2336G>A	p.Arg779His	missense_variant	12/16		NM_022168.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249336 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134774

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455194 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 724204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Aicardi-Goutieres syndrome 7 Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 03, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	Same nucleotide change resulting in same amino acid change has been previously reported multiole times as de novoo in similarly affected unrelated individuals (PMID:31898846, PS2, PS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000004, PM2). A different missense change at the same codon (p.Arg779Cys, p.Arg779Leu) has been reported as pathogenic (ClinVar ID: VCV000812532.2, PMID: 31898846, PM5). The variant was observed as assumed (i.e. paternity and maternity not confirmed) de novoo (3billion dataset, PM6). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.843, 3Cnet: 0.995, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	Aug 01, 2017	Missense variant previously described as pathogenic was identified in a patient with initially normal development, regression, severe ID, spasticity, scoliosis, episodic icterus and skin swelling. The variant was inherited from the healthy mother. -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The heterozygous p.Arg779His variant was identified by our study in one individual with Aicardi-Goutieres syndrome. Trio analysis showed this variant to be de novo. The p.Arg779His variant is believed to be pathogenic based on numberous reports by other laboratories in the literature and databases. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 14, 2021	Published functional studies demonstrate a damaging effect (gain of function that increases interferon signaling) (Rice et al., 2014); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29158550, 28553952, 24995871, 31130681, 24686847, 25777993, 27658362, 28475458, 29132962, 31623504, 31898846, 32042913, 32508843) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Aicardi-Goutieres syndrome 7;C4225427:Singleton-Merten syndrome 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 03, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 779 of the IFIH1 protein (p.Arg779His). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with Aicardi Goutieres syndrome (PMID: 31898846). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 137622). 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: 24686847, 26833990, 31898846). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

Immunodeficiency 95 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 25, 2024

- -

Clonus;C0151889:Hyperreflexia;C0948163:Abnormal cerebral white matter morphology;C1836830:Developmental regression;C2267233:Neonatal hypotonia;C4025723:Abnormal upper motor neuron morphology;C4520981:Abnormal basal ganglia morphology Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Singleton-Merten syndrome 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.68	D;D;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Uncertain	2.8	M;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.58	T
Polyphen		0.99	D;D;.
Vest4		0.93
MutPred		0.83		Loss of MoRF binding (P = 0.0311);Loss of MoRF binding (P = 0.0311);.;
MVP		0.91
MPC		0.11
ClinPred		0.93	D
GERP RS		5.6
Varity_R		0.36
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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; COSMIC: COSV55127542;