chr2-162267541-C-T

Variant names:

• chr2-162267541-C-T
• rs1990760
• NM_022168.4:c.2836G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_022168.4(IFIH1):​c.2836G>A​(p.Ala946Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.558 in 1,609,886 control chromosomes in the GnomAD database, including 262,583 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (18236 hom., cov: 33)
  • Exomes 𝑓: 0.57 (244347 hom.)
• Consequence: IFIH1 NM_022168.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.750
• Publications: 391 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=2.7895177E-5).
• BP6: Variant 2-162267541-C-T is Benign according to our data. Variant chr2-162267541-C-T is described in ClinVar as Benign. ClinVar VariationId is 261566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.605 is higher than 0.05.

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.2836G>A	p.Ala946Thr	missense	Exon 15 of 16	NP_071451.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFIH1	ENST00000649979.2	MANE Select	c.2836G>A	p.Ala946Thr	missense	Exon 15 of 16	ENSP00000497271.1
	IFIH1	ENST00000648433.1		c.2719G>A	p.Ala907Thr	missense	Exon 14 of 15	ENSP00000496816.1
	IFIH1	ENST00000679938.1		c.2524G>A	p.Ala842Thr	missense	Exon 14 of 15	ENSP00000505518.1

Frequencies

GnomAD3 genomes AF: 0.452 AC: 68651 AN: 151970 Hom.: 18242 Cov.: 33

Gnomad AFR AF: 0.186

Gnomad AMI AF: 0.574

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.462

Gnomad EAS AF: 0.195

Gnomad SAS AF: 0.514

Gnomad FIN AF: 0.568

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.610

Gnomad OTH AF: 0.471

GnomAD2 exomes AF: 0.502 AC: 125999 AN: 251196 AF XY: 0.515

Gnomad AFR exome AF: 0.175

Gnomad AMR exome AF: 0.424

Gnomad ASJ exome AF: 0.454

Gnomad EAS exome AF: 0.174

Gnomad FIN exome AF: 0.572

Gnomad NFE exome AF: 0.606

Gnomad OTH exome AF: 0.529

GnomAD4 exome AF: 0.569 AC: 830046 AN: 1457798 Hom.: 244347 Cov.: 34 AF XY: 0.570 AC XY: 413369 AN XY: 725498

African (AFR) AF: 0.166 AC: 5550 AN: 33452

American (AMR) AF: 0.426 AC: 19016 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.452 AC: 11797 AN: 26114

East Asian (EAS) AF: 0.202 AC: 8006 AN: 39684

South Asian (SAS) AF: 0.529 AC: 45573 AN: 86166

European-Finnish (FIN) AF: 0.575 AC: 30693 AN: 53388

Middle Eastern (MID) AF: 0.502 AC: 2890 AN: 5762

European-Non Finnish (NFE) AF: 0.609 AC: 674622 AN: 1108294

Other (OTH) AF: 0.529 AC: 31899 AN: 60260

GnomAD4 genome AF: 0.451 AC: 68647 AN: 152088 Hom.: 18236 Cov.: 33 AF XY: 0.448 AC XY: 33329 AN XY: 74366

African (AFR) AF: 0.185 AC: 7689 AN: 41472

American (AMR) AF: 0.442 AC: 6761 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.462 AC: 1602 AN: 3468

East Asian (EAS) AF: 0.195 AC: 1010 AN: 5170

South Asian (SAS) AF: 0.515 AC: 2489 AN: 4830

European-Finnish (FIN) AF: 0.568 AC: 6006 AN: 10574

Middle Eastern (MID) AF: 0.493 AC: 145 AN: 294

European-Non Finnish (NFE) AF: 0.610 AC: 41433 AN: 67976

Other (OTH) AF: 0.468 AC: 990 AN: 2114

Alfa AF: 0.548 Hom.: 112098

Bravo AF: 0.424

TwinsUK AF: 0.598 AC: 2217

ALSPAC AF: 0.605 AC: 2330

ESP6500AA AF: 0.185 AC: 816

ESP6500EA AF: 0.603 AC: 5185

ExAC AF: 0.505 AC: 61267

Asia WGS AF: 0.326 AC: 1136 AN: 3478

EpiCase AF: 0.596

EpiControl AF: 0.586

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Aicardi-Goutieres syndrome 7 (1)
-	-	1	Aicardi-Goutieres syndrome 7;C4225427:Singleton-Merten syndrome 1 (1)
-	-	1	Singleton-Merten syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	11
DANN	Benign	0.76
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.000028	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.75
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.19	N
REVEL	Benign	0.036
Sift	Benign	0.51	T
Sift4G	Benign	0.62	T
Polyphen		0.10	B
Vest4		0.017
MPC		0.024
ClinPred		0.0023	T
GERP RS		3.9
Varity_R		0.075
gMVP		0.23
Mutation Taster		=88/12	polymorphism (auto)

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: rs1990760; hg19: chr2-163124051; COSMIC: COSV55125663;