Genetic Variant IFNB1:p.Trp43Cys (chr9-21077741-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002176.4(IFNB1):c.129G>T(p.Trp43Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Consequence

IFNB1
NM_002176.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.22

Variant links:

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]

IFNB1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16908926).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IFNB1	NM_002176.4 link	c.129G>T	p.Trp43Cys	missense_variant	Exon 1 of 1	ENST00000380232.4	NP_002167.1	P01574A0A7R8GV38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IFNB1	ENST00000380232.4 link	c.129G>T	p.Trp43Cys	missense_variant	Exon 1 of 1	6	NM_002176.4	ENSP00000369581.2		P01574

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250630

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135412

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.57

CADD

Benign

9.1

DANN

Benign

0.96

DEOGEN2

Benign

0.091

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.71

M_CAP

Benign

0.0043

MetaRNN

Benign

0.17

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PrimateAI

Benign

0.20

PROVEAN

Benign

-1.3

REVEL

Benign

0.20

Sift

Benign

0.062

Sift4G

Benign

0.18

Polyphen

1.0

Vest4

0.23

MutPred

0.66

Loss of catalytic residue at L41 (P = 0.004);

MVP

0.44

MPC

0.019

ClinPred

0.68

GERP RS

-1.4

Varity_R

0.40

gMVP

0.25

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over