rs200810568

Positions:

• chr2-162272386-G-A
• chr2-162272386-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_022168.4(IFIH1):​c.2456C>T​(p.Ala819Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IFIH1 NM_022168.4 missense, splice_region
• Scores: Splicing: ADA: 0.4959
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.76

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain Helicase C-terminal (size 182) in uniprot entity IFIH1_HUMAN there are 6 pathogenic changes around while only 2 benign (75%) in NM_022168.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFIH1	NM_022168.4	c.2456C>T	p.Ala819Val	missense_variant, splice_region_variant	13/16	ENST00000649979.2	NP_071451.2
IFIH1	XM_047445407.1	c.1739C>T	p.Ala580Val	missense_variant, splice_region_variant	12/15		XP_047301363.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFIH1	ENST00000649979.2	c.2456C>T	p.Ala819Val	missense_variant, splice_region_variant	13/16		NM_022168.4	ENSP00000497271.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.51	D;D;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;D;D
M_CAP	Uncertain	0.086	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Uncertain	-0.035	T
MutationAssessor	Benign	1.3	L;L;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.3	.;D;.
REVEL	Uncertain	0.64
Sift	Uncertain	0.0020	.;D;.
Sift4G	Uncertain	0.0050	.;D;.
Polyphen		1.0	D;D;.
Vest4		0.67
MutPred		0.87		Loss of disorder (P = 0.0798);Loss of disorder (P = 0.0798);.;
MVP		0.85
MPC		0.19
ClinPred		0.96	D
GERP RS		4.8
Varity_R		0.90
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.50
dbscSNV1_RF	Benign	0.62
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-163128896;