14-75279924-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_005252.4(FOS):c.189G>A(p.Thr63=) 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
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.02

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 -15 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 id is 720688.Status of the report is criteria_provided_single_submitter, 1 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOS	NM_005252.4	c.189G>A	p.Thr63=	synonymous_variant	2/4	ENST00000303562.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOS	ENST00000303562.9	c.189G>A	p.Thr63=	synonymous_variant	2/4	1	NM_005252.4	P1

Frequencies

GnomAD3 genomes AF: 0.0210 AC: 3191 AN: 152098 Hom.: 114 Cov.: 32

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

GnomAD3 exomes AF: 0.00567 AC: 1421 AN: 250618 Hom.: 48 AF XY: 0.00407 AC XY: 551 AN XY: 135436

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 SAS exome AF: 0.0000981

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.: 29 AF XY: 0.00185 AC XY: 1347 AN XY: 727002

Gnomad4 AFR exome AF: 0.0786

Gnomad4 AMR exome AF: 0.00369

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000504

Gnomad4 OTH exome AF: 0.00447

GnomAD4 genome AF: 0.0210 AC: 3195 AN: 152216 Hom.: 115 Cov.: 32 AF XY: 0.0209 AC XY: 1552 AN XY: 74418

Gnomad4 AFR AF: 0.0734

Gnomad4 AMR AF: 0.00635

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.0171

Alfa AF: 0.0127 Hom.: 37

Bravo AF: 0.0243

ESP6500AA AF: 0.0697 AC: 307

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00705 AC: 856

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

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
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.30
Cadd	Benign	8.2
Dann	Benign	0.95
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.27	T
MetaRNN	Benign	0.0012	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D;D;D
PROVEAN	Benign	2.9	N
REVEL	Benign	0.048
Sift	Benign	1.0	T
Sift4G	Benign	0.88	T
MVP		0.31
ClinPred		0.014	T
GERP RS		-4.2

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

LitVar

Other links and lift over

dbSNP: rs76195634; hg19: chr14-75746627;