chr2-28404227-C-G

Position:

chr2-28404227-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_005253.4(FOSL2):c.223C>G(p.Pro75Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000669 in 1,614,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

FOSL2
NM_005253.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.85

Variant links:

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 links:

FOSL2 (HGNC:):

FOSL2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.046595246).

BS2

High AC in GnomAd4 at 48 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOSL2	NM_005253.4 linkuse as main transcript	c.223C>G	p.Pro75Ala	missense_variant	2/4	ENST00000264716.9	NP_005244.1	P15408-1Q9H5M2
FOSL2	XM_006711976.4 linkuse as main transcript	c.223C>G	p.Pro75Ala	missense_variant	2/4		XP_006712039.1
FOSL2	XM_006711977.4 linkuse as main transcript	c.106C>G	p.Pro36Ala	missense_variant	2/4		XP_006712040.1
FOSL2	XM_005264231.5 linkuse as main transcript	c.223C>G	p.Pro75Ala	missense_variant	2/5		XP_005264288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
FOSL2	ENST00000264716.9 linkuse as main transcript	c.223C>G	p.Pro75Ala	missense_variant	2/4	1	NM_005253.4	ENSP00000264716.4	P15408-1
FOSL2	ENST00000379619.5 linkuse as main transcript	c.148C>G	p.Pro50Ala	missense_variant	2/4	1		ENSP00000368939.1	P15408-2
FOSL2	ENST00000436647.1 linkuse as main transcript	c.106C>G	p.Pro36Ala	missense_variant	2/4	2		ENSP00000396497.1	C9JCN8
FOSL2	ENST00000460736.1 linkuse as main transcript	n.218C>G		non_coding_transcript_exon_variant	2/3	5

Frequencies

GnomAD3 genomes

AF:

0.000315

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00307

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000143

AC:

AN:

251466

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000925

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000410

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00125

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

AF:

0.000315

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.000444

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00307

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.000280

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.223C>G (p.P75A) alteration is located in exon 2 (coding exon 2) of the FOSL2 gene. This alteration results from a C to G substitution at nucleotide position 223, causing the proline (P) at amino acid position 75 to be replaced by an alanine (A). 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

0.079

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.41

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.24

.;T;T

Eigen

Benign

-0.054

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.87

D;D;D

M_CAP

Benign

0.011

MetaRNN

Benign

0.047

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.4

.;L;.

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.6

N;N;N

REVEL

Benign

0.12

Sift

Benign

0.080

T;T;T

Sift4G

Benign

0.12

T;T;T

Polyphen

0.013

.;B;.

Vest4

0.62

MutPred

0.23

.;Loss of glycosylation at P75 (P = 0.0216);.;

MVP

0.29

MPC

0.77

ClinPred

0.039

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.62

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over