Genetic Variant NM_022168.4:c.2455-7T>C (chr2-162272394-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_022168.4(IFIH1):c.2455-7T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

IFIH1
NM_022168.4 splice_region, intron

Scores

Splicing: ADA: 0.0002729

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.08

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Aicardi-Goutieres syndrome 7
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Illumina
IFIH1-related type 1 interferonopathy
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
Singleton-Merten syndrome 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
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

IFIH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFIH1	NM_022168.4	MANE Select	c.2455-7T>C		splice_region intron	N/A	NP_071451.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
IFIH1	ENST00000649979.2	MANE Select	c.2455-7T>C	splice_region intron	N/A	ENSP00000497271.1	Q9BYX4-1
IFIH1	ENST00000648433.1		c.2338-7T>C	splice_region intron	N/A	ENSP00000496816.1	A0A3B3IRK8
IFIH1	ENST00000679938.1		c.2143-7T>C	splice_region intron	N/A	ENSP00000505518.1	A0A7P0Z4A9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1457084

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724864

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33140

American (AMR)

AF:

0.00

AC:

AN:

43074

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25974

East Asian (EAS)

AF:

0.00

AC:

AN:

39646

South Asian (SAS)

AF:

0.0000116

AC:

AN:

85856

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53334

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110144

Other (OTH)

AF:

0.00

AC:

AN:

60178

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Benign

0.70

PhyloP100

2.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00027

dbscSNV1_RF

Benign

0.010

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over