NM_002176.4:c.180C>A

Variant names:

• chr9-21077690-G-T
• rs34130181
• NM_002176.4:c.180C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002176.4(IFNB1):​c.180C>A​(p.Asp60Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00267 in 1,613,950 control chromosomes in the GnomAD database, including 111 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. D60N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.015 (53 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (58 hom.)
• Consequence: IFNB1 NM_002176.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.225
• Publications: 0 publications found

Genes affected

IFNB1 (HGNC:5434): (interferon beta 1) This gene encodes a cytokine that belongs to the interferon family of signaling proteins, which are released as part of the innate immune response to pathogens. The protein encoded by this gene belongs to the type I class of interferons, which are important for defense against viral infections. In addition, type I interferons are involved in cell differentiation and anti-tumor defenses. Following secretion in response to a pathogen, type I interferons bind a homologous receptor complex and induce transcription of genes such as those encoding inflammatory cytokines and chemokines. Overactivation of type I interferon secretion is linked to autoimmune diseases. Mice deficient for this gene display several phenotypes including defects in B cell maturation and increased susceptibility to viral infection. [provided by RefSeq, Sep 2015]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002917558).
• BP6: Variant 9-21077690-G-T is Benign according to our data. Variant chr9-21077690-G-T is described in ClinVar as Benign. ClinVar VariationId is 780797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0502 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002176.4. 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
	IFNB1	NM_002176.4	MANE Select	c.180C>A	p.Asp60Glu	missense	Exon 1 of 1	NP_002167.1	P01574

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IFNB1	ENST00000380232.4	TSL:6 MANE Select	c.180C>A	p.Asp60Glu	missense	Exon 1 of 1	ENSP00000369581.2	P01574

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2228 AN: 152162 Hom.: 52 Cov.: 32

Gnomad AFR AF: 0.0503

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00767

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00909

GnomAD2 exomes AF: 0.00375 AC: 940 AN: 250692 AF XY: 0.00264

Gnomad AFR exome AF: 0.0513

Gnomad AMR exome AF: 0.00238

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00142 AC: 2078 AN: 1461670 Hom.: 58 Cov.: 32 AF XY: 0.00120 AC XY: 875 AN XY: 727126

African (AFR) AF: 0.0522 AC: 1746 AN: 33454

American (AMR) AF: 0.00277 AC: 124 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5766

European-Non Finnish (NFE) AF: 0.0000324 AC: 36 AN: 1111884

Other (OTH) AF: 0.00263 AC: 159 AN: 60386

GnomAD4 genome AF: 0.0147 AC: 2233 AN: 152280 Hom.: 53 Cov.: 32 AF XY: 0.0137 AC XY: 1019 AN XY: 74462

African (AFR) AF: 0.0503 AC: 2090 AN: 41570

American (AMR) AF: 0.00766 AC: 117 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68014

Other (OTH) AF: 0.00900 AC: 19 AN: 2112

Alfa AF: 0.0116 Hom.: 33

Bravo AF: 0.0174

ESP6500AA AF: 0.0511 AC: 225

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00455 AC: 552

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

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	0.097
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.8
DANN	Benign	0.54
DEOGEN2	Benign	0.047	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-2.3	N
PhyloP100		-0.23
PrimateAI	Benign	0.24	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.012
Sift	Benign	0.37	T
Sift4G	Benign	0.81	T
Polyphen		0.0	B
Vest4		0.015
MutPred		0.48		Gain of loop (P = 0.1069)
MVP		0.14
MPC		0.0063
ClinPred		0.0067	T
GERP RS		0.49
PromoterAI		0.0048	Neutral
Varity_R		0.098
gMVP		0.036
Mutation Taster		=99/1	polymorphism

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: rs34130181; hg19: chr9-21077689;