14-75281019-C-A

Variant names:

• chr14-75281019-C-A
• rs774449296
• NM_005252.4:c.738C>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_005252.4(FOS):​c.738C>A​(p.Asp246Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: FOS NM_005252.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0590

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06320724).
• BS2: High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOS	NM_005252.4	c.738C>A	p.Asp246Glu	missense_variant	Exon 4 of 4	ENST00000303562.9	NP_005243.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOS	ENST00000303562.9	c.738C>A	p.Asp246Glu	missense_variant	Exon 4 of 4	1	NM_005252.4	ENSP00000306245.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251294 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135830

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461706 Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14 AN XY: 727166

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000135

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 26, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.738C>A (p.D246E) alteration is located in exon 4 (coding exon 4) of the FOS gene. This alteration results from a C to A substitution at nucleotide position 738, causing the aspartic acid (D) at amino acid position 246 to be replaced by a glutamic acid (E). 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	0.066
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	9.0
DANN	Benign	0.74
DEOGEN2	Benign	0.37	T;.;.;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.64	T;T;T;T;T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.063	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.20	N;.;.;.;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.52	N;N;N;N;N
REVEL	Benign	0.059
Sift	Benign	0.27	T;T;T;T;T
Sift4G	Benign	0.88	T;T;T;T;T
Polyphen		0.0	B;.;.;.;.
Vest4		0.041
MutPred		0.19		Gain of catalytic residue at N245 (P = 0.0097);.;.;.;.;
MVP		0.52
MPC		0.053
ClinPred		0.017	T
GERP RS		-0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.049
gMVP		0.080

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: rs774449296; hg19: chr14-75747722;