rs376074455

chr2-162277463-G-Achr2-162277463-G-Cchr2-162277463-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_022168.4(IFIH1):c.1996C>T(p.Pro666Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,608,496 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P666A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: IFIH1 NM_022168.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.254

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03127125).
• BP6: Variant 2-162277463-G-A is Benign according to our data. Variant chr2-162277463-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 570847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IFIH1	NM_022168.4	c.1996C>T	p.Pro666Ser	missense_variant	10/16	ENST00000649979.2
IFIH1	XM_047445407.1	c.1279C>T	p.Pro427Ser	missense_variant	9/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IFIH1	ENST00000649979.2	c.1996C>T	p.Pro666Ser	missense_variant	10/16		NM_022168.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152002 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000409 AC: 10 AN: 244328 Hom.: 0 AF XY: 0.0000379 AC XY: 5 AN XY: 132060

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000332

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000274

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.0000199 AC: 29 AN: 1456494 Hom.: 0 Cov.: 29 AF XY: 0.0000179 AC XY: 13 AN XY: 724456

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000158

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152002 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74226

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000533 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2022

IFIH1: BP4 -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 17, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.73
Cadd	Benign	1.2
Dann	Benign	0.32
DEOGEN2	Benign	0.047	T;T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.20	N
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.031	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.4	L;L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.23	T
Polyphen		0.0020	B;B;.
Vest4		0.19
MutPred		0.19		Gain of phosphorylation at P666 (P = 0.0148);Gain of phosphorylation at P666 (P = 0.0148);.;
MVP		0.26
MPC		0.025
ClinPred		0.012	T
GERP RS		-0.098
Varity_R		0.019
gMVP		0.24

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: rs376074455; hg19: chr2-163133973;