14-75280809-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005252.4(FOS):c.528G>C(p.Lys176Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00542 in 1,614,080 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0055 (38 hom.)
• Consequence: FOS NM_005252.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.11

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009449899).
• BP6: Variant 14-75280809-G-C is Benign according to our data. Variant chr14-75280809-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 710469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 732 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOS	NM_005252.4	c.528G>C	p.Lys176Asn	missense_variant	4/4	ENST00000303562.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOS	ENST00000303562.9	c.528G>C	p.Lys176Asn	missense_variant	4/4	1	NM_005252.4	P1

Frequencies

GnomAD3 genomes AF: 0.00481 AC: 732 AN: 152124 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0223

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00591

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00468 AC: 1173 AN: 250786 Hom.: 5 AF XY: 0.00465 AC XY: 632 AN XY: 135840

Gnomad AFR exome AF: 0.000937

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00127

Gnomad FIN exome AF: 0.0201

Gnomad NFE exome AF: 0.00526

Gnomad OTH exome AF: 0.00327

GnomAD4 exome AF: 0.00549 AC: 8019 AN: 1461838 Hom.: 38 Cov.: 32 AF XY: 0.00527 AC XY: 3835 AN XY: 727218

Gnomad4 AFR exome AF: 0.000866

Gnomad4 AMR exome AF: 0.00242

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000962

Gnomad4 FIN exome AF: 0.0190

Gnomad4 NFE exome AF: 0.00585

Gnomad4 OTH exome AF: 0.00447

GnomAD4 genome AF: 0.00481 AC: 732 AN: 152242 Hom.: 4 Cov.: 32 AF XY: 0.00563 AC XY: 419 AN XY: 74436

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.00222

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0223

Gnomad4 NFE AF: 0.00591

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00116 Hom.: 3

Bravo AF: 0.00335

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00616 AC: 53

ExAC AF: 0.00457 AC: 555

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00371

EpiControl AF: 0.00433

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	FOS: BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.18
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;.;.;T;T
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D
MetaRNN	Benign	0.0094	T;T;T;T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	0.77	N;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.4	D;D;D;D;D
REVEL	Uncertain	0.29
Sift	Uncertain	0.0010	D;D;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.58
MutPred		0.41		Loss of ubiquitination at K176 (P = 0.0012);.;.;.;.;
MVP		0.91
MPC		2.3
ClinPred		0.034	T
GERP RS		4.5
Varity_R		0.93
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs138334429; hg19: chr14-75747512;