rs74162074

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_022168.4(IFIH1):c.445A>G(p.Arg149Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000186 in 1,573,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

IFIH1
NM_022168.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: -0.801

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.047371686).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000217 (33/152352) while in subpopulation AFR AF= 0.000433 (18/41582). AF 95% confidence interval is 0.000279. There are 0 homozygotes in gnomad4. There are 20 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFIH1	NM_022168.4 link	c.445A>G	p.Arg149Gly	missense_variant	Exon 1 of 16	ENST00000649979.2	NP_071451.2	Q9BYX4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFIH1	ENST00000649979.2 link	c.445A>G	p.Arg149Gly	missense_variant	Exon 1 of 16		NM_022168.4	ENSP00000497271.1		Q9BYX4-1

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000115

AC:

AN:

217294

Hom.:

AF XY:

0.000138

AC XY:

AN XY:

116280

show subpopulations

Gnomad AFR exome

AF:

0.000442

Gnomad AMR exome

AF:

0.0000692

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000159

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000183

AC:

260

AN:

1421086

Hom.:

Cov.:

AF XY:

0.000173

AC XY:

122

AN XY:

703202

show subpopulations

Gnomad4 AFR exome

AF:

0.000312

Gnomad4 AMR exome

AF:

0.0000778

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000221

Gnomad4 OTH exome

AF:

0.000103

GnomAD4 genome

AF:

0.000217

AC:

AN:

152352

Hom.:

Cov.:

AF XY:

0.000268

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000139

Hom.:

Bravo

AF:

0.000223

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000124

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Nov 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 03, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP4 -

not specified

Uncertain:1

Dec 03, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: IFIH1 c.445A>G (p.Arg149Gly) results in a non-conservative amino acid change located in the Death Domain, Fas (IPR011029) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 217294 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in IFIH1 causing Aicardi-Goutieres syndrome 7, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.445A>G in individuals affected with IFIH1-related conditions has been reported. At least one publication reports experimental evidence that this variant fails to activate a target gene promoter in vitro, however, to our knowledge IFIH1 is not yet associated with any loss-of-function gene-disease associations (example, Lamborn_2017). The following publication has been ascertained in the context of this evaluation (PMID: 28606988). ClinVar contains an entry for this variant (Variation ID: 541775). Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Benign:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

T;T;.;.

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.69

.;T;T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.047

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.7

M;M;.;M

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.3

.;N;.;D

REVEL

Benign

0.12

Sift

Benign

0.15

.;T;.;T

Sift4G

Benign

0.44

.;T;.;D

Polyphen

0.48

P;P;.;D

Vest4

0.17, 0.23

MVP

0.47

MPC

0.029

ClinPred

0.092

GERP RS

2.7

Varity_R

0.11

gMVP

0.56

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over