dbSNP rs4664463: IFIH1:c.874+109A>G (chr2-162293455-T-C) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_022168.4(IFIH1):c.874+109A>G variant causes a intron change. The variant allele was found at a frequency of 0.071 in 631,002 control chromosomes in the GnomAD database, including 6,632 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 4254 hom., cov: 32)

Exomes 𝑓: 0.045 ( 2378 hom. )

Consequence

IFIH1
NM_022168.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 3.75

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.34).

BP6

Variant 2-162293455-T-C is Benign according to our data. Variant chr2-162293455-T-C is described in ClinVar as [Benign]. Clinvar id is 1264951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.412 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFIH1	NM_022168.4 link	c.874+109A>G		intron_variant	Intron 4 of 15	ENST00000649979.2	NP_071451.2	Q9BYX4-1
IFIH1	XM_047445407.1 link	c.157+109A>G		intron_variant	Intron 3 of 14		XP_047301363.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFIH1	ENST00000649979.2 link	c.874+109A>G		intron_variant	Intron 4 of 15		NM_022168.4	ENSP00000497271.1		Q9BYX4-1

Frequencies

GnomAD3 genomes

AF:

0.152

AC:

22994

AN:

151750

Hom.:

4212

Cov.:

show subpopulations

Gnomad AFR

AF:

0.416

Gnomad AMI

AF:

0.00989

Gnomad AMR

AF:

0.250

Gnomad ASJ

AF:

0.00664

Gnomad EAS

AF:

0.111

Gnomad SAS

AF:

0.0240

Gnomad FIN

AF:

0.0121

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0131

Gnomad OTH

AF:

0.131

GnomAD4 exome

AF:

0.0452

AC:

21663

AN:

479132

Hom.:

2378

AF XY:

0.0411

AC XY:

10418

AN XY:

253272

show subpopulations

Gnomad4 AFR exome

AF:

0.412

Gnomad4 AMR exome

AF:

0.301

Gnomad4 ASJ exome

AF:

0.00845

Gnomad4 EAS exome

AF:

0.127

Gnomad4 SAS exome

AF:

0.0204

Gnomad4 FIN exome

AF:

0.0153

Gnomad4 NFE exome

AF:

0.0131

Gnomad4 OTH exome

AF:

0.0648

GnomAD4 genome

AF:

0.152

AC:

23112

AN:

151870

Hom.:

4254

Cov.:

AF XY:

0.152

AC XY:

11263

AN XY:

74254

show subpopulations

Gnomad4 AFR

AF:

0.417

Gnomad4 AMR

AF:

0.251

Gnomad4 ASJ

AF:

0.00664

Gnomad4 EAS

AF:

0.111

Gnomad4 SAS

AF:

0.0238

Gnomad4 FIN

AF:

0.0121

Gnomad4 NFE

AF:

0.0131

Gnomad4 OTH

AF:

0.137

Alfa

AF:

0.104

Hom.:

307

Asia WGS

AF:

0.122

AC:

424

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 03, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 27% of patients studied by a panel of primary immunodeficiencies. Number of patients: 26. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Benign

0.85

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