19-45470918-G-T

Variant names:

• chr19-45470918-G-T
• rs754837542
• NM_006732.3:c.416G>T

Variant summary

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

The NM_006732.3(FOSB):​c.416G>T​(p.Arg139Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FOSB NM_006732.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.91

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]

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 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 rank	MANE	Protein	UniProt
FOSB	NM_006732.3	c.416G>T	p.Arg139Leu	missense_variant	Exon 2 of 4	ENST00000353609.8	NP_006723.2
FOSB	NM_001114171.2	c.416G>T	p.Arg139Leu	missense_variant	Exon 2 of 3		NP_001107643.1
FOSB	NM_001411069.1	c.416G>T	p.Arg139Leu	missense_variant	Exon 2 of 5		NP_001397998.1
FOSB	XM_047438550.1	c.416G>T	p.Arg139Leu	missense_variant	Exon 2 of 4		XP_047294506.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOSB	ENST00000353609.8	c.416G>T	p.Arg139Leu	missense_variant	Exon 2 of 4	1	NM_006732.3	ENSP00000245919.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	.;.;.;T;.;.;T;.;.;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.82	T;T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.63	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.8	L;.;L;L;.;.;.;.;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-4.0	.;.;D;N;.;.;.;.;.;.
REVEL	Uncertain	0.37
Sift	Uncertain	0.0020	.;.;D;T;.;.;.;.;.;.
Sift4G	Benign	0.31	T;T;D;T;T;D;T;T;T;T
Polyphen		0.98	.;.;.;D;.;.;.;.;.;.
Vest4		0.34
MutPred		0.43		Loss of methylation at R139 (P = 0.004);.;Loss of methylation at R139 (P = 0.004);Loss of methylation at R139 (P = 0.004);.;Loss of methylation at R139 (P = 0.004);Loss of methylation at R139 (P = 0.004);.;.;.;
MVP		0.38
MPC		1.2
ClinPred		0.98	D
GERP RS		4.3
Varity_R		0.14
gMVP		0.77

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: rs754837542; hg19: chr19-45974176;