NM_022168.4:c.1379A>G

Variant names:

• chr2-162281473-T-C
• rs10930046
• NM_022168.4:c.1379A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022168.4(IFIH1):​c.1379A>G​(p.His460Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0475 in 1,611,932 control chromosomes in the GnomAD database, including 10,719 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H460Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.15 (4261 hom., cov: 32)
  • Exomes 𝑓: 0.037 (6458 hom.)
• Consequence: IFIH1 NM_022168.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.05
• Publications: 51 publications found

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 Gene-Disease associations (from GenCC):

• Aicardi-Goutieres syndrome 7

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Illumina, Labcorp Genetics (formerly Invitae), G2P
• Singleton-Merten syndrome 1

  Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Aicardi-Goutieres syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Singleton-Merten dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• immunodeficiency 95

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037111044).
• BP6: Variant 2-162281473-T-C is Benign according to our data. Variant chr2-162281473-T-C is described in ClinVar as Benign. ClinVar VariationId is 1170345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFIH1	NM_022168.4	c.1379A>G	p.His460Arg	missense_variant	Exon 7 of 16	ENST00000649979.2	NP_071451.2
IFIH1	XM_047445407.1	c.662A>G	p.His221Arg	missense_variant	Exon 6 of 15		XP_047301363.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFIH1	ENST00000649979.2	c.1379A>G	p.His460Arg	missense_variant	Exon 7 of 16		NM_022168.4	ENSP00000497271.1

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23046 AN: 151878 Hom.: 4215 Cov.: 32

Gnomad AFR AF: 0.415

Gnomad AMI AF: 0.00989

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.0248

Gnomad FIN AF: 0.0120

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0131

Gnomad OTH AF: 0.130

GnomAD2 exomes AF: 0.0967 AC: 24216 AN: 250532 AF XY: 0.0762

Gnomad AFR exome AF: 0.427

Gnomad AMR exome AF: 0.342

Gnomad ASJ exome AF: 0.00695

Gnomad EAS exome AF: 0.132

Gnomad FIN exome AF: 0.0148

Gnomad NFE exome AF: 0.0143

Gnomad OTH exome AF: 0.0619

GnomAD4 exome AF: 0.0366 AC: 53415 AN: 1459936 Hom.: 6458 Cov.: 30 AF XY: 0.0334 AC XY: 24280 AN XY: 726314

African (AFR) AF: 0.424 AC: 14133 AN: 33342

American (AMR) AF: 0.332 AC: 14788 AN: 44516

Ashkenazi Jewish (ASJ) AF: 0.00783 AC: 204 AN: 26068

East Asian (EAS) AF: 0.139 AC: 5529 AN: 39652

South Asian (SAS) AF: 0.0221 AC: 1908 AN: 86218

European-Finnish (FIN) AF: 0.0154 AC: 824 AN: 53346

Middle Eastern (MID) AF: 0.0141 AC: 81 AN: 5758

European-Non Finnish (NFE) AF: 0.0114 AC: 12660 AN: 1110776

Other (OTH) AF: 0.0546 AC: 3288 AN: 60260

GnomAD4 genome AF: 0.152 AC: 23167 AN: 151996 Hom.: 4261 Cov.: 32 AF XY: 0.152 AC XY: 11293 AN XY: 74338

African (AFR) AF: 0.416 AC: 17245 AN: 41438

American (AMR) AF: 0.251 AC: 3827 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.00692 AC: 24 AN: 3468

East Asian (EAS) AF: 0.124 AC: 638 AN: 5160

South Asian (SAS) AF: 0.0247 AC: 119 AN: 4826

European-Finnish (FIN) AF: 0.0120 AC: 127 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0131 AC: 888 AN: 67940

Other (OTH) AF: 0.136 AC: 287 AN: 2114

Alfa AF: 0.0575 Hom.: 5143

Bravo AF: 0.188

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.00986 AC: 38

ESP6500AA AF: 0.415 AC: 1828

ESP6500EA AF: 0.0142 AC: 122

ExAC AF: 0.0927 AC: 11244

Asia WGS AF: 0.128 AC: 445 AN: 3478

EpiCase AF: 0.0118

EpiControl AF: 0.0109

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Apr 03, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23441136) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 50% of patients studied by a panel of primary immunodeficiencies. Number of patients: 48. Only high quality variants are reported. -

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	14
DANN	Benign	0.46
DEOGEN2	Benign	0.057	T;T;.
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.035	.;T;T
MetaRNN	Benign	0.0037	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.4	N;N;.
PhyloP100		5.1
PrimateAI	Benign	0.48	T
PROVEAN	Benign	2.5	.;N;.
REVEL	Benign	0.11
Sift	Benign	1.0	.;T;.
Sift4G	Benign	1.0	.;T;.
Polyphen		0.0	B;B;.
Vest4		0.051
MPC		0.027
ClinPred		0.0054	T
GERP RS		5.9
Varity_R		0.18
gMVP		0.59
Mutation Taster		=84/16	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10930046; hg19: chr2-163137983; COSMIC: COSV55126041;