19-45471287-G-A

Position:

chr19-45471287-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006732.3(FOSB):c.541G>A(p.Asp181Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000128 in 1,562,802 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D181H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

FOSB
NM_006732.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.84

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
FOSB	NM_006732.3 linkuse as main transcript	c.541G>A	p.Asp181Asn	missense_variant	3/4	ENST00000353609.8
FOSB	NM_001411069.1 linkuse as main transcript	c.541G>A	p.Asp181Asn	missense_variant	3/5
FOSB	NM_001114171.2 linkuse as main transcript	c.447+338G>A		intron_variant
FOSB	XM_047438550.1 linkuse as main transcript	c.447+338G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOSB	ENST00000353609.8 linkuse as main transcript	c.541G>A	p.Asp181Asn	missense_variant	3/4	1	NM_006732.3	P1	P53539-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

7.09e-7

AC:

AN:

1410662

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

696948

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:

9.22e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000314

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 21, 2022

The c.541G>A (p.D181N) alteration is located in exon 3 (coding exon 3) of the FOSB gene. This alteration results from a G to A substitution at nucleotide position 541, causing the aspartic acid (D) at amino acid position 181 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Benign

-0.080

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.68

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.92

D;D;D;D;D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.54

D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.19

MutationAssessor

Benign

1.3

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

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.82

Sift4G

Benign

0.23

T;T;D;T;T;D;T

Polyphen

1.0

.;D;.;.;.;.;.

Vest4

0.27

MutPred

0.36

Gain of MoRF binding (P = 0.0552);Gain of MoRF binding (P = 0.0552);.;Gain of MoRF binding (P = 0.0552);.;.;.;

MVP

0.68

MPC

1.6

ClinPred

0.95

GERP RS

4.5

Varity_R

0.69

gMVP

0.75

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over