rs72650663

Variant names:

• chr2-162276886-G-A
• rs72650663
• NM_022168.4:c.2105C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022168.4(IFIH1):​c.2105C>T​(p.Thr702Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00331 in 1,612,420 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T702T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0034 (18 hom.)
• Consequence: IFIH1 NM_022168.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.177
• Publications: 14 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=0.0051235557).
• BP6: Variant 2-162276886-G-A is Benign according to our data. Variant chr2-162276886-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 541787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00248 (377/152120) while in subpopulation NFE AF = 0.00431 (293/67988). AF 95% confidence interval is 0.0039. There are 2 homozygotes in GnomAd4. There are 162 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022168.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFIH1	NM_022168.4	MANE Select	c.2105C>T	p.Thr702Ile	missense	Exon 11 of 16	NP_071451.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFIH1	ENST00000649979.2	MANE Select	c.2105C>T	p.Thr702Ile	missense	Exon 11 of 16	ENSP00000497271.1
	IFIH1	ENST00000648433.1		c.1988C>T	p.Thr663Ile	missense	Exon 10 of 15	ENSP00000496816.1
	IFIH1	ENST00000679938.1		c.1793C>T	p.Thr598Ile	missense	Exon 10 of 15	ENSP00000505518.1

Frequencies

GnomAD3 genomes AF: 0.00248 AC: 377 AN: 152002 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000628

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.000661

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00431

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00235 AC: 587 AN: 249830 AF XY: 0.00248

Gnomad AFR exome AF: 0.000432

Gnomad AMR exome AF: 0.00111

Gnomad ASJ exome AF: 0.00408

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00397

Gnomad OTH exome AF: 0.00246

GnomAD4 exome AF: 0.00340 AC: 4964 AN: 1460300 Hom.: 18 Cov.: 31 AF XY: 0.00343 AC XY: 2492 AN XY: 726402

African (AFR) AF: 0.000599 AC: 20 AN: 33402

American (AMR) AF: 0.00128 AC: 57 AN: 44506

Ashkenazi Jewish (ASJ) AF: 0.00398 AC: 104 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.000524 AC: 45 AN: 85802

European-Finnish (FIN) AF: 0.000955 AC: 51 AN: 53416

Middle Eastern (MID) AF: 0.00399 AC: 23 AN: 5760

European-Non Finnish (NFE) AF: 0.00399 AC: 4432 AN: 1111342

Other (OTH) AF: 0.00384 AC: 232 AN: 60342

GnomAD4 genome AF: 0.00248 AC: 377 AN: 152120 Hom.: 2 Cov.: 32 AF XY: 0.00218 AC XY: 162 AN XY: 74376

African (AFR) AF: 0.000626 AC: 26 AN: 41502

American (AMR) AF: 0.00157 AC: 24 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00404 AC: 14 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4828

European-Finnish (FIN) AF: 0.000661 AC: 7 AN: 10592

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00431 AC: 293 AN: 67988

Other (OTH) AF: 0.00332 AC: 7 AN: 2106

Alfa AF: 0.00336 Hom.: 1

Bravo AF: 0.00243

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00314 AC: 27

ExAC AF: 0.00219 AC: 266

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00536

EpiControl AF: 0.00523

ClinVar

Significance: Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

IFIH1: BP4, BS2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aicardi-Goutieres syndrome 7 Benign:1

Jun 30, 2020

Genetics and Molecular Pathology, SA Pathology

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 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

IFIH1-related disorder Benign:1

Feb 25, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.3
DANN	Benign	0.89
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.0	L
PhyloP100		-0.18
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.030
Sift	Benign	0.23	T
Sift4G	Benign	0.22	T
Polyphen		0.0	B
Vest4		0.15
MVP		0.15
MPC		0.025
ClinPred		0.0012	T
GERP RS		-5.6
Varity_R		0.076
gMVP		0.14
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs72650663; hg19: chr2-163133396;