chr9-21166467-G-T

Variant names:

• chr9-21166467-G-T
• rs140930380
• NM_002175.2:c.146C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002175.2(IFNA21):​c.146C>A​(p.Pro49His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,614,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P49R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: IFNA21 NM_002175.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.921
• Publications: 3 publications found

Genes affected

IFNA21 (HGNC:5424): (interferon alpha 21) This gene is a member of the alpha interferon gene cluster on the short arm of chromosome 9. Interferons are cytokines produced in response to viral infection that mediate the immune response and interfere with viral replication. The encoded protein is a type I interferon and may play a specific role in the antiviral response to rubella virus. [provided by RefSeq, Sep 2011]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.046853602).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002175.2. 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
	IFNA21	NM_002175.2	MANE Select	c.146C>A	p.Pro49His	missense	Exon 1 of 1	NP_002166.2	P01568

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNA21	ENST00000380225.1	TSL:6 MANE Select	c.146C>A	p.Pro49His	missense	Exon 1 of 1	ENSP00000369574.1	P01568

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000127 AC: 32 AN: 251432 AF XY: 0.000132

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000127 AC: 185 AN: 1461862 Hom.: 0 Cov.: 32 AF XY: 0.000132 AC XY: 96 AN XY: 727230

African (AFR) AF: 0.000149 AC: 5 AN: 33478

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00180 AC: 47 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86248

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000101 AC: 112 AN: 1111994

Other (OTH) AF: 0.000248 AC: 15 AN: 60394

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152260 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74450

African (AFR) AF: 0.000168 AC: 7 AN: 41556

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5172

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000348 Hom.: 0

Bravo AF: 0.000147

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.046	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.92
PrimateAI	Benign	0.28	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Benign	0.044
Sift	Uncertain	0.015	D
Sift4G	Benign	0.064	T
Polyphen		0.56	P
Vest4		0.25
MVP		0.27
MPC		0.024
ClinPred		0.24	T
GERP RS		2.0
PromoterAI		-0.0010	Neutral
Varity_R		0.32
gMVP		0.27
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs140930380; hg19: chr9-21166466;