rs1758567

Variant names:

• chr9-21440536-T-C
• rs1758567
• NM_024013.3:c.29T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024013.3(IFNA1):​c.29T>C​(p.Val10Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0508 in 1,596,994 control chromosomes in the GnomAD database, including 2,483 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.062 (233 hom., cov: 28)
  • Exomes 𝑓: 0.050 (2250 hom.)
• Consequence: IFNA1 NM_024013.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.926
• Publications: 10 publications found

Genes affected

IFNA1 (HGNC:5417): (interferon alpha 1) 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. This cytokine is upregulated in preeclamptic placentas and is thought to be a mediator of preeclampsia. [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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0072747767).
• BP6: Variant 9-21440536-T-C is Benign according to our data. Variant chr9-21440536-T-C is described in ClinVar as Benign. ClinVar VariationId is 771167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0956 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024013.3. 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
	IFNA1	NM_024013.3	MANE Select	c.29T>C	p.Val10Ala	missense	Exon 1 of 1	NP_076918.1	P01562

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNA1	ENST00000276927.3	TSL:6 MANE Select	c.29T>C	p.Val10Ala	missense	Exon 1 of 1	ENSP00000276927.1	P01562
	MIR31HG	ENST00000698348.1		n.719A>G		non_coding_transcript_exon	Exon 3 of 3
	MIR31HG	ENST00000698343.1		n.103-19844A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0620 AC: 9349 AN: 150730 Hom.: 231 Cov.: 28

Gnomad AFR AF: 0.0981

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0522

Gnomad ASJ AF: 0.0634

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0164

Gnomad FIN AF: 0.0259

Gnomad MID AF: 0.0987

Gnomad NFE AF: 0.0565

Gnomad OTH AF: 0.0710

GnomAD2 exomes AF: 0.0410 AC: 10145 AN: 247632 AF XY: 0.0407

Gnomad AFR exome AF: 0.0837

Gnomad AMR exome AF: 0.0329

Gnomad ASJ exome AF: 0.0472

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0265

Gnomad NFE exome AF: 0.0536

Gnomad OTH exome AF: 0.0532

GnomAD4 exome AF: 0.0496 AC: 71773 AN: 1446152 Hom.: 2250 Cov.: 32 AF XY: 0.0487 AC XY: 35012 AN XY: 719646

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0868 AC: 2684 AN: 30904

American (AMR) AF: 0.0375 AC: 1650 AN: 44020

Ashkenazi Jewish (ASJ) AF: 0.0533 AC: 1372 AN: 25746

East Asian (EAS) AF: 0.000580 AC: 23 AN: 39686

South Asian (SAS) AF: 0.0153 AC: 1313 AN: 85978

European-Finnish (FIN) AF: 0.0277 AC: 1477 AN: 53344

Middle Eastern (MID) AF: 0.108 AC: 605 AN: 5616

European-Non Finnish (NFE) AF: 0.0541 AC: 59636 AN: 1101366

Other (OTH) AF: 0.0506 AC: 3013 AN: 59492

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0621 AC: 9366 AN: 150842 Hom.: 233 Cov.: 28 AF XY: 0.0596 AC XY: 4393 AN XY: 73744

African (AFR) AF: 0.0982 AC: 3962 AN: 40366

American (AMR) AF: 0.0522 AC: 792 AN: 15186

Ashkenazi Jewish (ASJ) AF: 0.0634 AC: 220 AN: 3468

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5168

South Asian (SAS) AF: 0.0166 AC: 80 AN: 4816

European-Finnish (FIN) AF: 0.0259 AC: 275 AN: 10610

Middle Eastern (MID) AF: 0.0993 AC: 29 AN: 292

European-Non Finnish (NFE) AF: 0.0566 AC: 3842 AN: 67932

Other (OTH) AF: 0.0703 AC: 147 AN: 2092

Alfa AF: 0.0580 Hom.: 106

ExAC AF: 0.0474 AC: 5756

Asia WGS AF: 0.0180 AC: 61 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.2
DANN	Benign	0.15
DEOGEN2	Benign	0.036	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0012	N
LIST_S2	Benign	0.098	T
MetaRNN	Benign	0.0073	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-2.1	N
PhyloP100		-0.93
PrimateAI	Benign	0.26	T
PROVEAN	Benign	2.1	N
REVEL	Benign	0.037
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.0030
MPC		1.6
ClinPred		0.00048	T
GERP RS		1.3
PromoterAI		0.017	Neutral
Varity_R		0.023
gMVP		0.23
Mutation Taster		=98/2	polymorphism (auto)

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: rs1758567; hg19: chr9-21440535; COSMIC: COSV52806918;