9-21440995-C-G

Position:

• chr9-21440995-C-G

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.488C>G​(p.Ala163Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0931 in 1,590,596 control chromosomes in the GnomAD database, including 7,430 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.11 (1178 hom., cov: 28)
  • Exomes 𝑓: 0.091 (6252 hom.)
• Consequence: IFNA1 NM_024013.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.17

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=0.003593564).
• BP6: Variant 9-21440995-C-G is Benign according to our data. Variant chr9-21440995-C-G is described in ClinVar as [Benign]. Clinvar id is 768285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IFNA1	NM_024013.3	c.488C>G	p.Ala163Gly	missense_variant	1/1	ENST00000276927.3	NP_076918.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IFNA1	ENST00000276927.3	c.488C>G	p.Ala163Gly	missense_variant	1/1		NM_024013.3	ENSP00000276927	P1
MIR31HG	ENST00000698343.1	n.103-20303G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.113 AC: 16850 AN: 149738 Hom.: 1174 Cov.: 28

Gnomad AFR AF: 0.188

Gnomad AMI AF: 0.0903

Gnomad AMR AF: 0.0771

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.0429

Gnomad FIN AF: 0.0629

Gnomad MID AF: 0.140

Gnomad NFE AF: 0.0969

Gnomad OTH AF: 0.117

GnomAD3 exomes AF: 0.0818 AC: 18565 AN: 227076 Hom.: 1009 AF XY: 0.0812 AC XY: 10051 AN XY: 123844

Gnomad AFR exome AF: 0.177

Gnomad AMR exome AF: 0.0578

Gnomad ASJ exome AF: 0.108

Gnomad EAS exome AF: 0.000236

Gnomad SAS exome AF: 0.0447

Gnomad FIN exome AF: 0.0677

Gnomad NFE exome AF: 0.0971

Gnomad OTH exome AF: 0.0894

GnomAD4 exome AF: 0.0911 AC: 131210 AN: 1440740 Hom.: 6252 Cov.: 31 AF XY: 0.0900 AC XY: 64531 AN XY: 717094

Gnomad4 AFR exome AF: 0.187

Gnomad4 AMR exome AF: 0.0614

Gnomad4 ASJ exome AF: 0.109

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.0466

Gnomad4 FIN exome AF: 0.0650

Gnomad4 NFE exome AF: 0.0967

Gnomad4 OTH exome AF: 0.0900

GnomAD4 genome AF: 0.113 AC: 16871 AN: 149856 Hom.: 1178 Cov.: 28 AF XY: 0.108 AC XY: 7896 AN XY: 73112

Gnomad4 AFR AF: 0.188

Gnomad4 AMR AF: 0.0770

Gnomad4 ASJ AF: 0.105

Gnomad4 EAS AF: 0.000389

Gnomad4 SAS AF: 0.0432

Gnomad4 FIN AF: 0.0629

Gnomad4 NFE AF: 0.0969

Gnomad4 OTH AF: 0.116

Alfa AF: 0.106 Hom.: 166

Bravo AF: 0.119

ESP6500AA AF: 0.108 AC: 474

ESP6500EA AF: 0.0713 AC: 610

ExAC AF: 0.0833 AC: 10111

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.97	D
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Pathogenic	3.9	H
MutationTaster	Benign	0.10	P
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.20
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.013	D
Polyphen		0.93	P
Vest4		0.25
MPC		2.0
ClinPred		0.043	T
GERP RS		3.2
Varity_R		0.89
gMVP		0.16

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: rs28383794; hg19: chr9-21440994;