chr9-21187312-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). 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
• Publications: 26 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021068.4. 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
	IFNA4	NM_021068.4	MANE Select	c.220G>A	p.Ala74Thr	missense	Exon 1 of 1	NP_066546.1	P05014

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNA4	ENST00000421715.3	TSL:6 MANE Select	c.220G>A	p.Ala74Thr	missense	Exon 1 of 1	ENSP00000412897.1	P05014

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

GnomAD2 exomes AF: 0.616 AC: 154671 AN: 250914 AF XY: 0.614

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 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

African (AFR) AF: 0.603 AC: 20177 AN: 33470

American (AMR) AF: 0.677 AC: 30260 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.544 AC: 14203 AN: 26096

East Asian (EAS) AF: 0.862 AC: 34198 AN: 39694

South Asian (SAS) AF: 0.687 AC: 59222 AN: 86214

European-Finnish (FIN) AF: 0.554 AC: 29559 AN: 53402

Middle Eastern (MID) AF: 0.569 AC: 3277 AN: 5764

European-Non Finnish (NFE) AF: 0.565 AC: 627628 AN: 1111160

Other (OTH) AF: 0.592 AC: 35709 AN: 60350

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

African (AFR) AF: 0.604 AC: 24991 AN: 41354

American (AMR) AF: 0.622 AC: 9480 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.558 AC: 1937 AN: 3470

East Asian (EAS) AF: 0.850 AC: 4359 AN: 5130

South Asian (SAS) AF: 0.705 AC: 3385 AN: 4804

European-Finnish (FIN) AF: 0.547 AC: 5759 AN: 10530

Middle Eastern (MID) AF: 0.578 AC: 170 AN: 294

European-Non Finnish (NFE) AF: 0.563 AC: 38260 AN: 67920

Other (OTH) AF: 0.609 AC: 1284 AN: 2108

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

ClinVar submissions

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	0.077
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
PhyloP100		0.035
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
PromoterAI		0.0037	Neutral
Varity_R		0.12
gMVP		0.062
Mutation Taster		=100/0	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: rs1062571; hg19: chr9-21187311; COSMIC: COSV70179653; COSMIC: COSV70179653;