rs35744605

Variant names:

• chr2-162277580-C-A
• rs35744605
• NM_022168.4:c.1879G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-162277580-C-A
• chr2-162277580-C-G
• chr2-162277580-C-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 8P and 9B. PVS1 BP6 BS1 BS2

The NM_022168.4(IFIH1):​c.1879G>T​(p.Glu627*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00517 in 1,611,082 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0036 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (26 hom.)
• Consequence: IFIH1 NM_022168.4 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: 1.26
• Publications: 72 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: Likely_benign. The variant received -1 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• BP6: Variant 2-162277580-C-A is Benign according to our data. Variant chr2-162277580-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 377048.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00358 (545/152260) while in subpopulation NFE AF = 0.00614 (418/68024). AF 95% confidence interval is 0.00566. There are 4 homozygotes in GnomAd4. There are 235 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFIH1	NM_022168.4	c.1879G>T	p.Glu627*	stop_gained	Exon 10 of 16	ENST00000649979.2	NP_071451.2
IFIH1	XM_047445407.1	c.1162G>T	p.Glu388*	stop_gained	Exon 9 of 15		XP_047301363.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFIH1	ENST00000649979.2	c.1879G>T	p.Glu627*	stop_gained	Exon 10 of 16		NM_022168.4	ENSP00000497271.1

Frequencies

GnomAD3 genomes AF: 0.00358 AC: 545 AN: 152142 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00614

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00318 AC: 797 AN: 250898 AF XY: 0.00318

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00171

Gnomad NFE exome AF: 0.00585

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00534 AC: 7792 AN: 1458822 Hom.: 26 Cov.: 30 AF XY: 0.00526 AC XY: 3821 AN XY: 725876

African (AFR) AF: 0.000748 AC: 25 AN: 33418

American (AMR) AF: 0.00119 AC: 53 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.000306 AC: 8 AN: 26114

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39652

South Asian (SAS) AF: 0.000592 AC: 51 AN: 86202

European-Finnish (FIN) AF: 0.00216 AC: 115 AN: 53364

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5756

European-Non Finnish (NFE) AF: 0.00656 AC: 7282 AN: 1109430

Other (OTH) AF: 0.00425 AC: 256 AN: 60284

GnomAD4 genome AF: 0.00358 AC: 545 AN: 152260 Hom.: 4 Cov.: 32 AF XY: 0.00316 AC XY: 235 AN XY: 74446

African (AFR) AF: 0.00120 AC: 50 AN: 41554

American (AMR) AF: 0.00295 AC: 45 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00188 AC: 20 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00614 AC: 418 AN: 68024

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00477 Hom.: 5

Bravo AF: 0.00327

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00558 AC: 48

ExAC AF: 0.00326 AC: 396

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00589

EpiControl AF: 0.00427

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Sep 15, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS2, PS3, PVS1 -

Jan 10, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

IFIH1: BS2 -

Aicardi-Goutieres syndrome 7;C4225427:Singleton-Merten syndrome 1;C5676929:Immunodeficiency 95 Benign:2

Jul 30, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

-

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported in the literature in multiple individuals, largely in the context as a risk modifier for a variety of conditions such as type I diabetes and inflammatory bowel disease (Nejentsev 2009 PMID:19264985, Chistiakov 2010 PMID:20736039, Ostrowski 2016 PMID:28008999, Asgari 2017 PMID:28716935, Cananzi 2021 PMID:34185153). This variant is present in the Genome Aggregation Database (Highest reported MAF 0.6% (418/68032) including 3 homozygotes (https://gnomad.broadinstitute.org/variant/2-162277580-C-A?dataset=gnomad_r3). This variant is present in ClinVar, with several labs classifying this variant as Likely Benign or Benign (Variation ID:377048). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant creates a premature stop at this codon which results in an absent or abnormal protein. Functional studies support a deleterious effect of this variant (Shigemoto 2018 PMID:19324880, Cananzi 2021 PMID:34185153). However, these studies may not accurately represent in vivo biological function. Although an impact to the protein is expected due to this variant, the high presence of the variant and homozygotes in control cohorts as well as the multiple entries of Likely Benign or Benign in ClinVar suggest that the effect of this variant is more akin to a risk allele vs. a mendelian disease allele. Therefore, this variant is classified as Likely Benign. -

IFIH1-related immunodeficiency Uncertain:1

Sep 18, 2018

Undiagnosed Diseases Network, NIH

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Aug 17, 2022

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Aicardi-Goutieres syndrome 7 Benign:1

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Singleton-Merten syndrome 1 Benign:1

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

IFIH1-related disorder Benign:1

Sep 10, 2020

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.83	D
PhyloP100		1.3
Vest4		0.77
GERP RS		2.9
Mutation Taster		=123/77	disease causing (ClinVar)

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: rs35744605; hg19: chr2-163134090;