2-162277494-A-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS1

The NM_022168.4(IFIH1):c.1965T>A(p.Asp655Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000803 in 1,593,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. D655G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00050 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

IFIH1
NM_022168.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: -0.0650

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: PanelApp Australia, Illumina, Labcorp Genetics (formerly Invitae), G2P
Singleton-Merten syndrome 1
Inheritance: AD Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
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: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0053569376).

BP6

Variant 2-162277494-A-T is Benign according to our data. Variant chr2-162277494-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 541782.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000499 (76/152272) while in subpopulation AFR AF = 0.00164 (68/41576). AF 95% confidence interval is 0.00132. There are 0 homozygotes in GnomAd4. There are 39 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFIH1	NM_022168.4 link	c.1965T>A	p.Asp655Glu	missense_variant	Exon 10 of 16	ENST00000649979.2	NP_071451.2
IFIH1	XM_047445407.1 link	c.1248T>A	p.Asp416Glu	missense_variant	Exon 9 of 15		XP_047301363.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFIH1	ENST00000649979.2 link	c.1965T>A	p.Asp655Glu	missense_variant	Exon 10 of 16		NM_022168.4	ENSP00000497271.1

Frequencies

GnomAD3 genomes

AF:

0.000493

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

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:

0.00

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000170

AC:

AN:

246598

AF XY:

0.0000900

show subpopulations

Gnomad AFR exome

AF:

0.00250

Gnomad AMR exome

AF:

0.0000587

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000361

AC:

AN:

1440954

Hom.:

Cov.:

AF XY:

0.0000306

AC XY:

AN XY:

717982

show subpopulations

African (AFR)

AF:

0.00133

AC:

AN:

33042

American (AMR)

AF:

0.0000901

AC:

AN:

44410

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25972

East Asian (EAS)

AF:

0.00

AC:

AN:

39516

South Asian (SAS)

AF:

0.00

AC:

AN:

85726

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53232

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.00000183

AC:

AN:

1093652

Other (OTH)

AF:

0.0000335

AC:

AN:

59668

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000499

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.00164

AC:

AN:

41576

American (AMR)

AF:

0.000327

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68000

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000546

Hom.:

Bravo

AF:

0.000544

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000239

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Benign:1

Dec 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

IFIH1-related disorder

Benign:1

Mar 17, 2020

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.66

CADD

Benign

1.9

(source)

DANN

Benign

0.37

DEOGEN2

Benign

0.042

T;T;.

Eigen

Benign

-0.93

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.40

.;T;T

M_CAP

Benign

0.0055

MetaRNN

Benign

0.0054

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.9

L;L;.

PhyloP100

-0.065

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.26

.;N;.

REVEL

Benign

0.0050

Sift

Benign

0.43

.;T;.

Sift4G

Benign

0.53

.;T;.

Polyphen

0.18

B;B;.

Vest4

0.13

MutPred

0.34

Gain of catalytic residue at D655 (P = 0.1025);Gain of catalytic residue at D655 (P = 0.1025);.;

MVP

0.38

MPC

0.029

ClinPred

0.0027

GERP RS

0.76

Varity_R

0.022

gMVP

0.13

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over