rs200833729

Variant names:

• chr2-162272245-G-A
• rs200833729
• NM_022168.4:c.2597C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_022168.4(IFIH1):​c.2597C>T​(p.Pro866Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00032 in 1,611,814 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P866S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (6 hom.)
• Consequence: IFIH1 NM_022168.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.131
• Publications: 8 publications found

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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.031043172).
• BP6: Variant 2-162272245-G-A is Benign according to our data. Variant chr2-162272245-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 541773.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000276 (42/152190) while in subpopulation AMR AF = 0.000523 (8/15288). AF 95% confidence interval is 0.00026. There are 0 homozygotes in GnomAd4. There are 27 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AD,AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFIH1	NM_022168.4	MANE Select	c.2597C>T	p.Pro866Leu	missense	Exon 13 of 16	NP_071451.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFIH1	ENST00000649979.2	MANE Select	c.2597C>T	p.Pro866Leu	missense	Exon 13 of 16	ENSP00000497271.1
	IFIH1	ENST00000648433.1		c.2480C>T	p.Pro827Leu	missense	Exon 12 of 15	ENSP00000496816.1
	IFIH1	ENST00000679938.1		c.2285C>T	p.Pro762Leu	missense	Exon 12 of 15	ENSP00000505518.1

Frequencies

GnomAD3 genomes AF: 0.000270 AC: 41 AN: 152072 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000398 AC: 99 AN: 248756 AF XY: 0.000476

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000497

Gnomad ASJ exome AF: 0.000799

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000516

Gnomad OTH exome AF: 0.000991

GnomAD4 exome AF: 0.000325 AC: 474 AN: 1459624 Hom.: 6 Cov.: 30 AF XY: 0.000353 AC XY: 256 AN XY: 726014

African (AFR) AF: 0.000240 AC: 8 AN: 33398

American (AMR) AF: 0.000517 AC: 23 AN: 44454

Ashkenazi Jewish (ASJ) AF: 0.000844 AC: 22 AN: 26076

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.000256 AC: 22 AN: 86018

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53254

Middle Eastern (MID) AF: 0.0129 AC: 74 AN: 5748

European-Non Finnish (NFE) AF: 0.000257 AC: 286 AN: 1110760

Other (OTH) AF: 0.000647 AC: 39 AN: 60268

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74414

African (AFR) AF: 0.0000722 AC: 3 AN: 41542

American (AMR) AF: 0.000523 AC: 8 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000280 AC: 19 AN: 67978

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.000481 Hom.: 0

Bravo AF: 0.000249

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000396 AC: 48

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	Aicardi-Goutieres syndrome 7;C4225427:Singleton-Merten syndrome 1 (1)
-	-	1	IFIH1-related disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.13
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.098
Sift	Benign	0.12	T
Sift4G	Benign	0.18	T
Polyphen		0.94	P
Vest4		0.30
MVP		0.52
MPC		0.032
ClinPred		0.11	T
GERP RS		4.9
Varity_R		0.15
gMVP		0.47
Mutation Taster		=74/26	polymorphism

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

Other links and lift over

dbSNP: rs200833729; hg19: chr2-163128755; COSMIC: COSV55130895;