2-28404209-A-G

Position:

• chr2-28404209-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005253.4(FOSL2):​c.205A>G​(p.Ile69Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: FOSL2 NM_005253.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.14

Genes affected

FOSL2 (HGNC:3798): (FOS like 2, 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. [provided by RefSeq, Jul 2014]

FOSL2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36524534).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOSL2	NM_005253.4	c.205A>G	p.Ile69Val	missense_variant	2/4	ENST00000264716.9	NP_005244.1
FOSL2	XM_006711976.4	c.205A>G	p.Ile69Val	missense_variant	2/4		XP_006712039.1
FOSL2	XM_006711977.4	c.88A>G	p.Ile30Val	missense_variant	2/4		XP_006712040.1
FOSL2	XM_005264231.5	c.205A>G	p.Ile69Val	missense_variant	2/5		XP_005264288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOSL2	ENST00000264716.9	c.205A>G	p.Ile69Val	missense_variant	2/4	1	NM_005253.4	ENSP00000264716.4
FOSL2	ENST00000379619.5	c.130A>G	p.Ile44Val	missense_variant	2/4	1		ENSP00000368939.1
FOSL2	ENST00000436647.1	c.88A>G	p.Ile30Val	missense_variant	2/4	2		ENSP00000396497.1
FOSL2	ENST00000460736.1	n.200A>G		non_coding_transcript_exon_variant	2/3	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

Oct 06, 2021

The c.205A>G (p.I69V) alteration is located in exon 2 (coding exon 2) of the FOSL2 gene. This alteration results from a A to G substitution at nucleotide position 205, causing the isoleucine (I) at amino acid position 69 to be replaced by a valine (V). 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	Pathogenic	0.59
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	.;T;T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	D;T;T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.7	.;L;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.34	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.40	T;T;T
Sift4G	Benign	0.36	T;T;T
Polyphen		0.96	.;D;.
Vest4		0.43
MutPred		0.39		.;Gain of catalytic residue at I69 (P = 0.0537);.;
MVP		0.37
MPC		1.7
ClinPred		0.87	D
GERP RS		5.3
Varity_R		0.12
gMVP		0.43

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-28627076;