19-45472813-C-G

Position:

• chr19-45472813-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_006732.3(FOSB):​c.818C>G​(p.Pro273Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: FOSB NM_006732.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.79

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 (HGNC:):

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.116018265).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOSB	NM_006732.3	c.818C>G	p.Pro273Arg	missense_variant	4/4	ENST00000353609.8	NP_006723.2
FOSB	NM_001114171.2	c.710C>G	p.Pro237Arg	missense_variant	3/3		NP_001107643.1
FOSB	NM_001411069.1	c.712-34C>G		intron_variant			NP_001397998.1
FOSB	XM_047438550.1	c.604-34C>G		intron_variant			XP_047294506.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOSB	ENST00000353609.8	c.818C>G	p.Pro273Arg	missense_variant	4/4	1	NM_006732.3	ENSP00000245919.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251326 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135864

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461864 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727238

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: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 25, 2022

The c.818C>G (p.P273R) alteration is located in exon 4 (coding exon 4) of the FOSB gene. This alteration results from a C to G substitution at nucleotide position 818, causing the proline (P) at amino acid position 273 to be replaced by an arginine (R). 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	Benign	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.68	.;.;D;.;.;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.060
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.82	T;T;T;T;T;T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.12	T;T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	0.55	.;.;N;.;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-2.1	.;N;N;.;N;.
REVEL	Benign	0.081
Sift	Uncertain	0.0080	.;D;D;.;D;.
Sift4G	Uncertain	0.0050	D;D;D;D;D;D
Polyphen		0.0060	.;.;B;.;.;.
Vest4		0.14
MutPred		0.40		.;.;Loss of glycosylation at P273 (P = 0.0584);.;.;.;
MVP		0.26
MPC		0.83
ClinPred		0.13	T
GERP RS		3.7
Varity_R		0.20
gMVP		0.38

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

Other links and lift over

dbSNP: rs1338731100; hg19: chr19-45976071;