Genetic Variant FOS:p.Thr63Thr (chr14-75279924-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005252.4(FOS):c.189G>A(p.Thr63Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00393 in 1,613,634 control chromosomes in the GnomAD database, including 228 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 115 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 113 hom. )

Consequence

FOS
NM_005252.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.02

Publications

4 publications found

Variant links:

Genes affected

FOS (HGNC:3796): (Fos proto-oncogene, 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. In some cases, expression of the FOS gene has also been associated with apoptotic cell death. [provided by RefSeq, Jul 2008]

FOS Gene-Disease associations (from GenCC):

Berardinelli-Seip congenital lipodystrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

FOS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0011785626).

BP6

Variant 14-75279924-G-A is Benign according to our data. Variant chr14-75279924-G-A is described in ClinVar as Benign. ClinVar VariationId is 720688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.02 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0712 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005252.4. 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
	FOS	NM_005252.4	MANE Select	c.189G>A	p.Thr63Thr	synonymous	Exon 2 of 4	NP_005243.1	P01100-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
FOS	ENST00000303562.9	TSL:1 MANE Select	c.189G>A	p.Thr63Thr	synonymous	Exon 2 of 4	ENSP00000306245.4	P01100-1
FOS	ENST00000554212.5	TSL:4	c.160G>A	p.Gly54Ser	missense	Exon 2 of 3	ENSP00000452443.1	G3V5N9
FOS	ENST00000871987.1		c.189G>A	p.Thr63Thr	synonymous	Exon 2 of 4	ENSP00000542046.1

Frequencies

GnomAD3 genomes

AF:

0.0210

AC:

3191

AN:

152098

Hom.:

114

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0736

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00635

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.0173

GnomAD2 exomes

AF:

0.00567

AC:

1421

AN:

250618

AF XY:

0.00407

show subpopulations

Gnomad AFR exome

AF:

0.0789

Gnomad AMR exome

AF:

0.00318

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000795

Gnomad OTH exome

AF:

0.00278

GnomAD4 exome

AF:

0.00215

AC:

3147

AN:

1461418

Hom.:

113

Cov.:

AF XY:

0.00185

AC XY:

1347

AN XY:

727002

show subpopulations

African (AFR)

AF:

0.0786

AC:

2632

AN:

33474

American (AMR)

AF:

0.00369

AC:

165

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26084

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000186

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53374

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000504

AC:

AN:

1111746

Other (OTH)

AF:

0.00447

AC:

270

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

173

346

520

693

866

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

234

312

390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0210

AC:

3195

AN:

152216

Hom.:

115

Cov.:

AF XY:

0.0209

AC XY:

1552

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.0734

AC:

3050

AN:

41542

American (AMR)

AF:

0.00635

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000415

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68014

Other (OTH)

AF:

0.0171

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

154

308

461

615

769

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0197

Hom.:

Bravo

AF:

0.0243

ESP6500AA

AF:

0.0697

AC:

307

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00705

AC:

856

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.30

CADD

Benign

8.2

(source)

DANN

Benign

0.95

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.27

MetaRNN

Benign

0.0012

MetaSVM

Benign

-1.0

PhyloP100

-1.0

PROVEAN

Benign

2.9

REVEL

Benign

0.048

Sift

Benign

1.0

Sift4G

Benign

0.88

MVP

0.31

ClinPred

0.014

GERP RS

-4.2

PromoterAI

0.0055

Neutral

(source)

Mutation Taster

=285/15

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over