rs35667974

chr2-162268127-T-Cchr2-162268127-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_022168.4(IFIH1):c.2767A>G(p.Ile923Val) variant causes a missense change. The variant allele was found at a frequency of 0.0164 in 1,609,266 control chromosomes in the GnomAD database, including 279 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I923T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.011 (16 hom., cov: 32)
  • Exomes 𝑓: 0.017 (263 hom.)
• Consequence: IFIH1 NM_022168.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.71

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007831156).
• BP6: Variant 2-162268127-T-C is Benign according to our data. Variant chr2-162268127-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 474954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-162268127-T-C is described in Lovd as [Likely_benign]. Variant chr2-162268127-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0114 (1739/152342) while in subpopulation NFE AF= 0.0188 (1281/68034). AF 95% confidence interval is 0.018. There are 16 homozygotes in gnomad4. There are 801 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 16 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFIH1	NM_022168.4	c.2767A>G	p.Ile923Val	missense_variant	14/16	ENST00000649979.2
IFIH1	XM_047445407.1	c.2050A>G	p.Ile684Val	missense_variant	13/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFIH1	ENST00000649979.2	c.2767A>G	p.Ile923Val	missense_variant	14/16		NM_022168.4	P1

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1738 AN: 152224 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00350

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0208

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0188

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.0113 AC: 2789 AN: 247356 Hom.: 37 AF XY: 0.0109 AC XY: 1450 AN XY: 133634

Gnomad AFR exome AF: 0.00248

Gnomad AMR exome AF: 0.00221

Gnomad ASJ exome AF: 0.00986

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000170

Gnomad FIN exome AF: 0.0205

Gnomad NFE exome AF: 0.0183

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.0169 AC: 24651 AN: 1456924 Hom.: 263 Cov.: 30 AF XY: 0.0163 AC XY: 11801 AN XY: 724584

Gnomad4 AFR exome AF: 0.00250

Gnomad4 AMR exome AF: 0.00226

Gnomad4 ASJ exome AF: 0.0110

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000200

Gnomad4 FIN exome AF: 0.0200

Gnomad4 NFE exome AF: 0.0201

Gnomad4 OTH exome AF: 0.0123

GnomAD4 genome AF: 0.0114 AC: 1739 AN: 152342 Hom.: 16 Cov.: 32 AF XY: 0.0108 AC XY: 801 AN XY: 74496

Gnomad4 AFR AF: 0.00349

Gnomad4 AMR AF: 0.00300

Gnomad4 ASJ AF: 0.0109

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0208

Gnomad4 NFE AF: 0.0188

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.0161 Hom.: 34

Bravo AF: 0.0100

TwinsUK AF: 0.0194 AC: 72

ALSPAC AF: 0.0192 AC: 74

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.0163 AC: 140

ExAC AF: 0.0115 AC: 1399

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jan 20, 2017

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 15, 2021

This variant is associated with the following publications: (PMID: 20736039, 20668468, 19264985, 19324880, 27720759, 28501801, 28973304, 28658209) -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

IFIH1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 18, 2022

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	0.12
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.071	T;T;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
MetaRNN	Benign	0.0078	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.47	T
Polyphen		0.96	D;D;.
Vest4		0.29
MPC		0.18
ClinPred		0.027	T
GERP RS		5.1
Varity_R		0.30
gMVP		0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs35667974; hg19: chr2-163124637;