14-75280647-C-G

Variant names:

• chr14-75280647-C-G
• rs1024053802
• NM_005252.4:c.481C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005252.4(FOS):​c.481C>G​(p.Leu161Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L161L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FOS NM_005252.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.08
• Publications: 0 publications found

Genes affected

FOS (HGNC:3796): (Fos 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. In some cases, expression of the FOS gene has also been associated with apoptotic cell death. [provided by RefSeq, Jul 2008]

FOS Gene-Disease associations (from GenCC):

• Berardinelli-Seip congenital lipodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005252.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOS	NM_005252.4	MANE Select	c.481C>G	p.Leu161Val	missense	Exon 3 of 4	NP_005243.1	P01100-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOS	ENST00000303562.9	TSL:1 MANE Select	c.481C>G	p.Leu161Val	missense	Exon 3 of 4	ENSP00000306245.4	P01100-1
	FOS	ENST00000871987.1		c.481C>G	p.Leu161Val	missense	Exon 3 of 4	ENSP00000542046.1
	FOS	ENST00000944924.1		c.481C>G	p.Leu161Val	missense	Exon 3 of 4	ENSP00000614983.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Uncertain	0.087	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.1
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.49
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.38		Gain of MoRF binding (P = 0.0946)
MVP		0.83
MPC		2.2
ClinPred		0.99	D
GERP RS		4.4
PromoterAI		-0.038	Neutral
Varity_R		0.91
gMVP		0.69
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1024053802; hg19: chr14-75747350;