14-75280102-A-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_005252.4(FOS):c.367A>G(p.Ile123Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,613,986 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (6 hom.)
• Consequence: FOS NM_005252.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.32

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0071657896).
• BP6: Variant 14-75280102-A-G is Benign according to our data. Variant chr14-75280102-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 770618.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 221 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOS	NM_005252.4	c.367A>G	p.Ile123Val	missense_variant	2/4	ENST00000303562.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOS	ENST00000303562.9	c.367A>G	p.Ile123Val	missense_variant	2/4	1	NM_005252.4	P1

Frequencies

GnomAD3 genomes AF: 0.00145 AC: 221 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00240

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00174 AC: 434 AN: 249206 Hom.: 1 AF XY: 0.00166 AC XY: 225 AN XY: 135144

Gnomad AFR exome AF: 0.000255

Gnomad AMR exome AF: 0.00231

Gnomad ASJ exome AF: 0.000299

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.000647

Gnomad NFE exome AF: 0.00283

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.00218 AC: 3187 AN: 1461676 Hom.: 6 Cov.: 36 AF XY: 0.00207 AC XY: 1507 AN XY: 727138

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00217

Gnomad4 ASJ exome AF: 0.000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000429

Gnomad4 FIN exome AF: 0.000714

Gnomad4 NFE exome AF: 0.00259

Gnomad4 OTH exome AF: 0.00182

GnomAD4 genome AF: 0.00144 AC: 220 AN: 152310 Hom.: 0 Cov.: 33 AF XY: 0.00141 AC XY: 105 AN XY: 74482

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00238

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00249 Hom.: 2

Bravo AF: 0.00152

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00182 AC: 221

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00245

EpiControl AF: 0.00273

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	16
Dann	Benign	0.76
Eigen	Benign	-0.068
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.23	T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0072	T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	0.97	N;N;N;N;N
PROVEAN	Benign	1.3	N;N
REVEL	Uncertain	0.34
Sift	Benign	0.17	T;T
Sift4G	Benign	0.48	T;T
MVP		0.93
ClinPred		0.057	T
GERP RS		6.0

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: rs150427794; hg19: chr14-75746805;