rs72650663

chr2-162276886-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong 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. 15/21 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: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.177

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 Benign. Variant got -16 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 id is 541787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-162276886-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFIH1	NM_022168.4	c.2105C>T	p.Thr702Ile	missense_variant	11/16	ENST00000649979.2
IFIH1	XM_047445407.1	c.1388C>T	p.Thr463Ile	missense_variant	10/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFIH1	ENST00000649979.2	c.2105C>T	p.Thr702Ile	missense_variant	11/16		NM_022168.4	P1

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

GnomAD3 exomes AF: 0.00235 AC: 587 AN: 249830 Hom.: 0 AF XY: 0.00248 AC XY: 334 AN XY: 134912

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 SAS exome AF: 0.000766

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

Gnomad4 AFR exome AF: 0.000599

Gnomad4 AMR exome AF: 0.00128

Gnomad4 ASJ exome AF: 0.00398

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000524

Gnomad4 FIN exome AF: 0.000955

Gnomad4 NFE exome AF: 0.00399

Gnomad4 OTH exome AF: 0.00384

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

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.00404

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000661

Gnomad4 NFE AF: 0.00431

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00360 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: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	IFIH1: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Aicardi-Goutieres syndrome 7 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

Jun 30, 2020

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

IFIH1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 25, 2020

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 v4.3

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;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.073	N
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.0051	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.0	L;L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
Polyphen		0.0	B;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs72650663; hg19: chr2-163133396;