9-21440536-T-C

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• 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

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

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFNA1	NM_024013.3	c.29T>C	p.Val10Ala	missense_variant	Exon 1 of 1	ENST00000276927.3	NP_076918.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFNA1	ENST00000276927.3	c.29T>C	p.Val10Ala	missense_variant	Exon 1 of 1	6	NM_024013.3	ENSP00000276927.1

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

GnomAD3 exomes AF: 0.0410 AC: 10145 AN: 247632 Hom.: 327 AF XY: 0.0407 AC XY: 5461 AN XY: 134084

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 SAS exome AF: 0.0128

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

Gnomad4 AFR exome AF: 0.0868

Gnomad4 AMR exome AF: 0.0375

Gnomad4 ASJ exome AF: 0.0533

Gnomad4 EAS exome AF: 0.000580

Gnomad4 SAS exome AF: 0.0153

Gnomad4 FIN exome AF: 0.0277

Gnomad4 NFE exome AF: 0.0541

Gnomad4 OTH exome AF: 0.0506

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

Gnomad4 AFR AF: 0.0982

Gnomad4 AMR AF: 0.0522

Gnomad4 ASJ AF: 0.0634

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.0166

Gnomad4 FIN AF: 0.0259

Gnomad4 NFE AF: 0.0566

Gnomad4 OTH AF: 0.0703

Alfa AF: 0.0629 Hom.: 68

ExAC AF: 0.0474 AC: 5756

Asia WGS AF: 0.0180 AC: 61 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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
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
Varity_R		0.023
gMVP		0.23

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

Publications

LitVar

Other links and lift over

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