9-21187312-C-T

Variant names:

• chr9-21187312-C-T
• rs1062571
• NM_021068.4:c.220G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021068.4(IFNA4):​c.220G>A​(p.Ala74Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.586 in 1,612,590 control chromosomes in the GnomAD database, including 280,134 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A74V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.59 (27043 hom., cov: 30)
  • Exomes 𝑓: 0.58 (253091 hom.)
• Consequence: IFNA4 NM_021068.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0350

Genes affected

IFNA4 (HGNC:5425): (interferon alpha 4) Predicted to enable cytokine activity and type I interferon receptor binding activity. Predicted to be involved in several processes, including B cell activation; lymphocyte activation involved in immune response; and positive regulation of peptidyl-serine phosphorylation of STAT protein. Predicted to be located in extracellular region. Predicted to be active in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0726089E-6).
• BP6: Variant 9-21187312-C-T is Benign according to our data. Variant chr9-21187312-C-T is described in ClinVar as [Benign]. Clinvar id is 1230680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.829 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFNA4	NM_021068.4	c.220G>A	p.Ala74Thr	missense_variant	Exon 1 of 1	ENST00000421715.3	NP_066546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFNA4	ENST00000421715.3	c.220G>A	p.Ala74Thr	missense_variant	Exon 1 of 1	6	NM_021068.4	ENSP00000412897.1

Frequencies

GnomAD3 genomes AF: 0.594 AC: 90083 AN: 151636 Hom.: 27007 Cov.: 30

Gnomad AFR AF: 0.604

Gnomad AMI AF: 0.602

Gnomad AMR AF: 0.623

Gnomad ASJ AF: 0.558

Gnomad EAS AF: 0.849

Gnomad SAS AF: 0.704

Gnomad FIN AF: 0.547

Gnomad MID AF: 0.563

Gnomad NFE AF: 0.563

Gnomad OTH AF: 0.604

GnomAD3 exomes AF: 0.616 AC: 154671 AN: 250914 Hom.: 48831 AF XY: 0.614 AC XY: 83225 AN XY: 135632

Gnomad AFR exome AF: 0.609

Gnomad AMR exome AF: 0.683

Gnomad ASJ exome AF: 0.539

Gnomad EAS exome AF: 0.861

Gnomad SAS exome AF: 0.688

Gnomad FIN exome AF: 0.550

Gnomad NFE exome AF: 0.559

Gnomad OTH exome AF: 0.599

GnomAD4 exome AF: 0.585 AC: 854233 AN: 1460836 Hom.: 253091 Cov.: 76 AF XY: 0.587 AC XY: 426323 AN XY: 726692

Gnomad4 AFR exome AF: 0.603

Gnomad4 AMR exome AF: 0.677

Gnomad4 ASJ exome AF: 0.544

Gnomad4 EAS exome AF: 0.862

Gnomad4 SAS exome AF: 0.687

Gnomad4 FIN exome AF: 0.554

Gnomad4 NFE exome AF: 0.565

Gnomad4 OTH exome AF: 0.592

GnomAD4 genome AF: 0.594 AC: 90173 AN: 151754 Hom.: 27043 Cov.: 30 AF XY: 0.597 AC XY: 44257 AN XY: 74144

Gnomad4 AFR AF: 0.604

Gnomad4 AMR AF: 0.622

Gnomad4 ASJ AF: 0.558

Gnomad4 EAS AF: 0.850

Gnomad4 SAS AF: 0.705

Gnomad4 FIN AF: 0.547

Gnomad4 NFE AF: 0.563

Gnomad4 OTH AF: 0.609

Alfa AF: 0.570 Hom.: 10579

Bravo AF: 0.601

TwinsUK AF: 0.555 AC: 2059

ALSPAC AF: 0.567 AC: 2185

ExAC AF: 0.610 AC: 74075

Asia WGS AF: 0.777 AC: 2701 AN: 3478

EpiCase AF: 0.567

EpiControl AF: 0.562

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

- -

Apr 26, 2019

GeneDx

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	0.077
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	6.0
DANN	Benign	0.84
DEOGEN2	Benign	0.016	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.026
Sift	Benign	0.091	T
Sift4G	Benign	0.46	T
Polyphen		0.0010	B
Vest4		0.0030
MPC		0.61
ClinPred		0.0060	T
GERP RS		1.1
Varity_R		0.12
gMVP		0.062

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: rs1062571; hg19: chr9-21187311; COSMIC: COSV70179653; COSMIC: COSV70179653;