2-28404161-G-A

Variant names:

• chr2-28404161-G-A
• rs560133888
• NM_005253.4:c.157G>A

Variant summary

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

The NM_005253.4(FOSL2):​c.157G>A​(p.Ala53Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: FOSL2 NM_005253.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.14

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]

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
FOSL2	NM_005253.4	c.157G>A	p.Ala53Thr	missense_variant	Exon 2 of 4	ENST00000264716.9	NP_005244.1
FOSL2	XM_006711976.4	c.157G>A	p.Ala53Thr	missense_variant	Exon 2 of 4		XP_006712039.1
FOSL2	XM_006711977.4	c.40G>A	p.Ala14Thr	missense_variant	Exon 2 of 4		XP_006712040.1
FOSL2	XM_005264231.5	c.157G>A	p.Ala53Thr	missense_variant	Exon 2 of 5		XP_005264288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOSL2	ENST00000264716.9	c.157G>A	p.Ala53Thr	missense_variant	Exon 2 of 4	1	NM_005253.4	ENSP00000264716.4
FOSL2	ENST00000379619.5	c.82G>A	p.Ala28Thr	missense_variant	Exon 2 of 4	1		ENSP00000368939.1
FOSL2	ENST00000436647.1	c.40G>A	p.Ala14Thr	missense_variant	Exon 2 of 4	2		ENSP00000396497.1
FOSL2	ENST00000460736.1	n.152G>A		non_coding_transcript_exon_variant	Exon 2 of 3	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 04, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.157G>A (p.A53T) alteration is located in exon 2 (coding exon 2) of the FOSL2 gene. This alteration results from a G to A substitution at nucleotide position 157, causing the alanine (A) at amino acid position 53 to be replaced by a threonine (T). 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	0.91
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	.;D;T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.1	.;M;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Uncertain	0.41
Sift	Benign	0.062	T;D;T
Sift4G	Benign	0.11	T;D;T
Polyphen		0.96	.;D;.
Vest4		0.61
MutPred		0.38		.;Gain of sheet (P = 0.0827);.;
MVP		0.60
MPC		1.1
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.71
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: rs560133888; hg19: chr2-28627028; COSMIC: COSV99268273;