11-65896828-C-G

Variant names:

• chr11-65896828-C-G
• rs201410689
• NM_005438.5:c.278G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005438.5(FOSL1):​c.278G>C​(p.Arg93Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R93C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FOSL1 NM_005438.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.12
• Publications: 0 publications found

Genes affected

FOSL1 (HGNC:13718): (FOS like 1, 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. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33164257).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005438.5. 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
	FOSL1	NM_005438.5	MANE Select	c.278G>C	p.Arg93Pro	missense	Exon 2 of 4	NP_005429.1	A0A0S2Z595
	FOSL1	NM_001300844.2		c.278G>C	p.Arg93Pro	missense	Exon 2 of 3	NP_001287773.1	E9PPX2
	FOSL1	NM_001300855.2		c.278G>C	p.Arg93Pro	missense	Exon 2 of 4	NP_001287784.1	E9PKL5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOSL1	ENST00000312562.7	TSL:1 MANE Select	c.278G>C	p.Arg93Pro	missense	Exon 2 of 4	ENSP00000310170.2	P15407-1
	FOSL1	ENST00000531493.5	TSL:1	c.278G>C	p.Arg93Pro	missense	Exon 2 of 3	ENSP00000436276.1	E9PPX2
	FOSL1	ENST00000913992.1		c.275G>C	p.Arg92Pro	missense	Exon 2 of 4	ENSP00000584051.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458094 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 724930

African (AFR) AF: 0.00 AC: 0 AN: 33334

American (AMR) AF: 0.00 AC: 0 AN: 44360

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25910

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.00 AC: 0 AN: 86122

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53328

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5562

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109692

Other (OTH) AF: 0.00 AC: 0 AN: 60164

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.84	D
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.1
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.24
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.99	D
Vest4		0.55
MutPred		0.32		Loss of methylation at R93 (P = 0.0352)
MVP		0.94
MPC		0.50
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.71
gMVP		0.76
Mutation Taster		=51/49	polymorphism

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

Other links and lift over

dbSNP: rs201410689; hg19: chr11-65664299;