Genetic Variant ENSG00000258740:n.447+336G>T (chr14-75278744-C-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_ModerateBS1BS2

The ENST00000789958.1(ENSG00000258740):n.447+336G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00319 in 513,928 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0078 ( 13 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 3 hom. )

Consequence

ENSG00000258740
ENST00000789958.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.45

Publications

1 publications found

Variant links:

Genes affected

ENSG00000258740 (HGNC:58290):

ENSG00000258740 links:

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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.37).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00776 (1182/152298) while in subpopulation AFR AF = 0.0259 (1076/41570). AF 95% confidence interval is 0.0246. There are 13 homozygotes in GnomAd4. There are 568 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOS	NM_005252.4 link	c.-239C>A		upstream_gene_variant		ENST00000303562.9	NP_005243.1	P01100-1Q6FG41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOS	ENST00000303562.9 link	c.-239C>A		upstream_gene_variant		1	NM_005252.4	ENSP00000306245.4		P01100-1

Frequencies

GnomAD3 genomes

AF:

0.00774

AC:

1178

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0259

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00308

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.000220

Gnomad OTH

AF:

0.00813

GnomAD4 exome

AF:

0.00127

AC:

458

AN:

361630

Hom.:

Cov.:

AF XY:

0.00123

AC XY:

235

AN XY:

190724

show subpopulations

African (AFR)

AF:

0.0264

AC:

194

AN:

7336

American (AMR)

AF:

0.00291

AC:

AN:

10306

Ashkenazi Jewish (ASJ)

AF:

0.00261

AC:

AN:

10716

East Asian (EAS)

AF:

0.00

AC:

AN:

20324

South Asian (SAS)

AF:

0.000201

AC:

AN:

39754

European-Finnish (FIN)

AF:

0.000807

AC:

AN:

24794

Middle Eastern (MID)

AF:

0.00502

AC:

AN:

1594

European-Non Finnish (NFE)

AF:

0.000345

AC:

AN:

225770

Other (OTH)

AF:

0.00437

AC:

AN:

21036

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.516

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.00776

AC:

1182

AN:

152298

Hom.:

Cov.:

AF XY:

0.00763

AC XY:

568

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0259

AC:

1076

AN:

41570

American (AMR)

AF:

0.00307

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000221

AC:

AN:

68022

Other (OTH)

AF:

0.00804

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

116

174

232

290

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00265

Hom.:

Bravo

AF:

0.00842

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

0.43

(source)

DANN

Benign

0.63

PhyloP100

-2.5

PromoterAI

-0.33

Neutral

(source)

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over