2-162288184-T-C

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.1046A>G(p.Lys349Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00256 in 1,612,674 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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. K349M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0018 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (36 hom.)
• Consequence: IFIH1 NM_022168.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.33

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=0.0059061646).
• BP6: Variant 2-162288184-T-C is Benign according to our data. Variant chr2-162288184-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 541789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-162288184-T-C is described in Lovd as [Benign]. Variant chr2-162288184-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00176 (267/152054) while in subpopulation SAS AF= 0.0213 (103/4832). AF 95% confidence interval is 0.018. There are 3 homozygotes in gnomad4. There are 143 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFIH1	NM_022168.4	c.1046A>G	p.Lys349Arg	missense_variant	5/16	ENST00000649979.2
IFIH1	XM_047445407.1	c.329A>G	p.Lys110Arg	missense_variant	4/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFIH1	ENST00000649979.2	c.1046A>G	p.Lys349Arg	missense_variant	5/16		NM_022168.4	P1

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 268 AN: 151936 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0215

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00158

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00315 AC: 790 AN: 250826 Hom.: 8 AF XY: 0.00429 AC XY: 581 AN XY: 135562

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0187

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00144

Gnomad OTH exome AF: 0.00197

GnomAD4 exome AF: 0.00264 AC: 3856 AN: 1460620 Hom.: 36 Cov.: 31 AF XY: 0.00322 AC XY: 2340 AN XY: 726652

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0198

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00171

Gnomad4 OTH exome AF: 0.00264

GnomAD4 genome AF: 0.00176 AC: 267 AN: 152054 Hom.: 3 Cov.: 32 AF XY: 0.00192 AC XY: 143 AN XY: 74324

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00249

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0213

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00158

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00147 Hom.: 0

Bravo AF: 0.00119

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00353 AC: 429

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00186

EpiControl AF: 0.00160

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

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

-

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 13, 2021

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

-

- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

IFIH1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 21, 2019

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	0.070
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.070	T;T;.
Eigen	Benign	0.014
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.87	D
MetaRNN	Benign	0.0059	T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.43	N;N;.
MutationTaster	Benign	0.86	D;D
PrimateAI	Benign	0.35	T
Polyphen		0.34	B;B;.
Vest4		0.19
MVP		0.71
MPC		0.024
ClinPred		0.019	T
GERP RS		6.0
Varity_R		0.15
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs72650664; hg19: chr2-163144694;