chr11-65900309-T-C

Position:

• chr11-65900309-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005438.5(FOSL1):​c.31A>G​(p.Ser11Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000366 in 1,091,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: FOSL1 NM_005438.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.253

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14858934).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOSL1	NM_005438.5	c.31A>G	p.Ser11Gly	missense_variant	1/4	ENST00000312562.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOSL1	ENST00000312562.7	c.31A>G	p.Ser11Gly	missense_variant	1/4	1	NM_005438.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000366 AC: 4 AN: 1091714 Hom.: 0 Cov.: 30 AF XY: 0.00000386 AC XY: 2 AN XY: 518304

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000112

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000227

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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

Mar 30, 2024

The c.31A>G (p.S11G) alteration is located in exon 1 (coding exon 1) of the FOSL1 gene. This alteration results from a A to G substitution at nucleotide position 31, causing the serine (S) at amino acid position 11 to be replaced by a glycine (G). 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	0.084
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	.;T;.;T
Eigen	Benign	-0.068
Eigen_PC	Benign	0.017
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.46	T;T;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.9	L;L;.;.
MutationTaster	Benign	0.56	D;D;D;D;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.2	N;N;N;N
REVEL	Uncertain	0.39
Sift	Benign	0.11	T;D;D;D
Sift4G	Pathogenic	0.0	D;T;T;D
Polyphen		0.78	.;P;.;.
Vest4		0.23
MutPred		0.14		Loss of phosphorylation at S11 (P = 0.0147);Loss of phosphorylation at S11 (P = 0.0147);Loss of phosphorylation at S11 (P = 0.0147);Loss of phosphorylation at S11 (P = 0.0147);
MVP		0.72
MPC		0.42
ClinPred		0.72	D
GERP RS		4.4
Varity_R		0.13
gMVP		0.29

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: rs1479161684; hg19: chr11-65667780; COSMIC: COSV57027763;