dbSNP rs771108595: FOSB:p.Ile224Val (chr19-45472665-A-G) – 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_006732.3(FOSB):c.670A>G(p.Ile224Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

FOSB
NM_006732.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.78

Variant links:

Genes affected

FOSB (HGNC:3797): (FosB proto-oncogene, AP-1 transcription factor subunit) The Fos gene family consists of 4 members: FOS, FOSB, FOSL1, and FOSL2. These genes encode leucine zipper proteins that can dimerize with proteins of the JUN family, thereby forming the transcription factor complex AP-1. As such, the FOS proteins have been implicated as regulators of cell proliferation, differentiation, and transformation. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

FOSB links:

ERCC1 (HGNC:3433): (ERCC excision repair 1, endonuclease non-catalytic subunit) The product of this gene functions in the nucleotide excision repair pathway, and is required for the repair of DNA lesions such as those induced by UV light or formed by electrophilic compounds including cisplatin. The encoded protein forms a heterodimer with the XPF endonuclease (also known as ERCC4), and the heterodimeric endonuclease catalyzes the 5' incision in the process of excising the DNA lesion. The heterodimeric endonuclease is also involved in recombinational DNA repair and in the repair of inter-strand crosslinks. Mutations in this gene result in cerebrooculofacioskeletal syndrome, and polymorphisms that alter expression of this gene may play a role in carcinogenesis. Multiple transcript variants encoding different isoforms have been found for this gene. The last exon of this gene overlaps with the CD3e molecule, epsilon associated protein gene on the opposite strand. [provided by RefSeq, Oct 2009]

ERCC1 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=0.1357036).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOSB	NM_006732.3 link	c.670A>G	p.Ile224Val	missense_variant	Exon 4 of 4	ENST00000353609.8	NP_006723.2	P53539-1A0A024R0P6
FOSB	NM_001114171.2 link	c.562A>G	p.Ile188Val	missense_variant	Exon 3 of 3		NP_001107643.1	P53539-2
FOSB	NM_001411069.1 link	c.670A>G	p.Ile224Val	missense_variant	Exon 4 of 5		NP_001397998.1
FOSB	XM_047438550.1 link	c.562A>G	p.Ile188Val	missense_variant	Exon 3 of 4		XP_047294506.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOSB	ENST00000353609.8 link	c.670A>G	p.Ile224Val	missense_variant	Exon 4 of 4	1	NM_006732.3	ENSP00000245919.3		P53539-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1447456

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

719602

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.04e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Uncertain

0.025

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

.;.;.;T;.;.;T;.;.

Eigen

Benign

-0.059

Eigen_PC

Benign

0.075

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.82

T;T;T;T;T;T;T;T;T

M_CAP

Benign

0.053

MetaRNN

Benign

0.14

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.55

MutationAssessor

Benign

0.81

L;.;.;L;.;.;.;.;.

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.69

.;.;N;N;.;N;.;.;.

REVEL

Benign

0.10

Sift

Benign

0.030

.;.;D;T;.;T;.;.;.

Sift4G

Benign

0.20

T;T;T;T;T;T;T;T;T

Polyphen

0.16

.;.;.;B;.;.;.;.;.

Vest4

0.24

MutPred

0.22

Gain of catalytic residue at I224 (P = 0.0244);.;.;Gain of catalytic residue at I224 (P = 0.0244);.;.;Gain of catalytic residue at I224 (P = 0.0244);.;.;

MVP

0.60

MPC

0.77

ClinPred

0.47

GERP RS

4.8

Varity_R

0.087

gMVP

0.51

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over