rs139714761

Variant names:

• chr2-162281540-A-G
• rs139714761
• NM_022168.4:c.1312T>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1 BP6 BS1

The NM_022168.4(IFIH1):​c.1312T>C​(p.Ser438Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000587 in 1,601,778 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: IFIH1 NM_022168.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 3.22
• Publications: 6 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: 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

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_022168.4
• BP6: Variant 2-162281540-A-G is Benign according to our data. Variant chr2-162281540-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 445430.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000552 (80/1449794) while in subpopulation EAS AF = 0.000354 (14/39500). AF 95% confidence interval is 0.000214. There are 0 homozygotes in GnomAdExome4. There are 38 alleles in the male GnomAdExome4 subpopulation. Median coverage is 28. This position passed quality control check.

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.1312T>C	p.Ser438Pro	missense	Exon 7 of 16	NP_071451.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFIH1	ENST00000649979.2	MANE Select	c.1312T>C	p.Ser438Pro	missense	Exon 7 of 16	ENSP00000497271.1	Q9BYX4-1
	IFIH1	ENST00000648433.1		c.1312T>C	p.Ser438Pro	missense	Exon 7 of 15	ENSP00000496816.1	A0A3B3IRK8
	IFIH1	ENST00000679938.1		c.1000T>C	p.Ser334Pro	missense	Exon 6 of 15	ENSP00000505518.1	A0A7P0Z4A9

Frequencies

GnomAD3 genomes AF: 0.0000921 AC: 14 AN: 151984 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000148 AC: 36 AN: 243424 AF XY: 0.000106

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00101

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000165

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000552 AC: 80 AN: 1449794 Hom.: 0 Cov.: 28 AF XY: 0.0000527 AC XY: 38 AN XY: 721454

African (AFR) AF: 0.00 AC: 0 AN: 33040

American (AMR) AF: 0.00 AC: 0 AN: 43994

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25902

East Asian (EAS) AF: 0.000354 AC: 14 AN: 39500

South Asian (SAS) AF: 0.00 AC: 0 AN: 85560

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53114

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.0000571 AC: 63 AN: 1103160

Other (OTH) AF: 0.0000501 AC: 3 AN: 59828

GnomAD4 genome AF: 0.0000921 AC: 14 AN: 151984 Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7 AN XY: 74218

African (AFR) AF: 0.00 AC: 0 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 67952

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000129 Hom.: 0

Bravo AF: 0.000110

ExAC AF: 0.0000826 AC: 10

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	2	not provided (5)
-	-	1	Aicardi-Goutieres syndrome 7;C4225427:Singleton-Merten syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Pathogenic	2.9	M
PhyloP100		3.2
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.88
MVP		0.74
MPC		0.21
ClinPred		0.89	D
GERP RS		4.8
Varity_R		0.97
gMVP		0.87
Mutation Taster		=40/60	disease causing

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

Other links and lift over

dbSNP: rs139714761; hg19: chr2-163138050;