chr9-21385086-T-C

Variant names:

• chr9-21385086-T-C
• rs1255943506
• NM_000605.4:c.244A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000605.4(IFNA2):​c.244A>G​(p.Met82Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: IFNA2 NM_000605.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.361
• Publications: 1 publications found

Genes affected

IFNA2 (HGNC:5423): (interferon alpha 2) This gene is a member of the alpha interferon gene cluster on chromosome 9. The encoded cytokine is a member of the type I interferon family that is produced in response to viral infection as a key part of the innate immune response with potent antiviral, antiproliferative and immunomodulatory properties. This cytokine, like other type I interferons, binds a plasma membrane receptor made of IFNAR1 and IFNAR2 that is ubiquitously expressed, and thus is able to act on virtually all body cells. The encoded protein is effective in reducing the symptoms and duration of the common cold and in treating many types of cancer, including some hematological malignancies and solid tumors. A deficiency of type I interferon in the blood is thought to be a hallmark of severe COVID-19 and may provide a rationale for a combined therapeutic approach. [provided by RefSeq, Aug 2020]

MIR31HG (HGNC:37187): (MIR31 host gene) This gene produces a long non-coding RNA that acts as a host gene for miR-31. This transcript may be involved in cellular pluripotency and regulate the differentiation of myoblasts and other tissues. This RNA was found to interact with Polycomb repressive proteins to repression transcription of genes involves in cell senescence. [provided by RefSeq, Dec 2017]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.078679204).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000605.4. 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
	IFNA2	NM_000605.4	MANE Select	c.244A>G	p.Met82Val	missense	Exon 1 of 1	NP_000596.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNA2	ENST00000380206.4	TSL:6 MANE Select	c.244A>G	p.Met82Val	missense	Exon 1 of 1	ENSP00000369554.2	P01563
	MIR31HG	ENST00000698342.1		n.726-4727A>G		intron	N/A
	MIR31HG	ENST00000773559.1		n.372-5058A>G		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251410 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 6.84e-7 AC: 1 AN: 1461820 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727210

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111982

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	13
DANN	Benign	0.71
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.032	N
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.079	T
MetaSVM	Benign	-0.96	T
PhyloP100		-0.36
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.036
Sift	Benign	0.25	T
Sift4G	Benign	0.27	T
Vest4		0.067
MutPred		0.59		Loss of catalytic residue at V78 (P = 0.0146)
MVP		0.16
MPC		0.0030
ClinPred		0.10	T
GERP RS		-0.89
PromoterAI		0.0055	Neutral
gMVP		0.12
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs1255943506; hg19: chr9-21385085;