chr19-45472665-A-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_006732.3(FOSB):c.670A>T(p.Ile224Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000594 in 1,599,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000059 ( 0 hom. )

Consequence

FOSB
NM_006732.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.78

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

cerebrooculofacioskeletal syndrome 4
Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
Cockayne syndrome type 2
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
COFS syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ERCC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.24697506).

BS2

High AC in GnomAd4 at 10 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006732.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FOSB	NM_006732.3	MANE Select	c.670A>T	p.Ile224Phe	missense	Exon 4 of 4	NP_006723.2	P53539-1
FOSB	NM_001114171.2		c.562A>T	p.Ile188Phe	missense	Exon 3 of 3	NP_001107643.1	P53539-2
FOSB	NM_001411069.1		c.670A>T	p.Ile224Phe	missense	Exon 4 of 5	NP_001397998.1	P53539-11

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FOSB	ENST00000353609.8	TSL:1 MANE Select	c.670A>T	p.Ile224Phe	missense	Exon 4 of 4	ENSP00000245919.3	P53539-1
FOSB	ENST00000417353.6	TSL:1	c.562A>T	p.Ile188Phe	missense	Exon 3 of 3	ENSP00000407207.1	P53539-2
FOSB	ENST00000591858.5	TSL:1	c.553A>T	p.Ile185Phe	missense	Exon 4 of 4	ENSP00000466530.1	P53539-3

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152164

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:

0.0000882

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000544

AC:

AN:

238864

AF XY:

0.0000770

show subpopulations

Gnomad AFR exome

AF:

0.000128

Gnomad AMR exome

AF:

0.0000320

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000915

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000587

AC:

AN:

1447456

Hom.:

Cov.:

AF XY:

0.0000570

AC XY:

AN XY:

719602

show subpopulations

African (AFR)

AF:

0.0000307

AC:

AN:

32622

American (AMR)

AF:

0.0000488

AC:

AN:

40990

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25362

East Asian (EAS)

AF:

0.00

AC:

AN:

39556

South Asian (SAS)

AF:

0.00

AC:

AN:

84726

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53026

Middle Eastern (MID)

AF:

0.000178

AC:

AN:

5616

European-Non Finnish (NFE)

AF:

0.0000714

AC:

AN:

1105946

Other (OTH)

AF:

0.0000336

AC:

AN:

59612

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68006

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000642

ExAC

AF:

0.0000824

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.030

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.79

Eigen

Benign

0.17

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.86

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.25

MetaSVM

Benign

-0.46

MutationAssessor

Benign

0.81

PhyloP100

1.8

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.27

Sift

Uncertain

0.014

Sift4G

Benign

0.062

Polyphen

0.68

Vest4

0.49

MVP

0.73

MPC

1.9

ClinPred

0.093

GERP RS

4.8

Varity_R

0.30

gMVP

0.73

Mutation Taster

=40/60

disease causing

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over