chr14-75280102-A-G

Variant names:

• chr14-75280102-A-G
• rs150427794
• NM_005252.4:c.367A>G

Variant summary

Our verdict is Benign. The variant received -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. 13/18 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
• Publications: 4 publications found

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]

FOS Gene-Disease associations (from GenCC):

• Berardinelli-Seip congenital lipodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 770618.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005252.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOS	NM_005252.4	MANE Select	c.367A>G	p.Ile123Val	missense	Exon 2 of 4	NP_005243.1	P01100-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOS	ENST00000303562.9	TSL:1 MANE Select	c.367A>G	p.Ile123Val	missense	Exon 2 of 4	ENSP00000306245.4	P01100-1
	FOS	ENST00000871987.1		c.367A>G	p.Ile123Val	missense	Exon 2 of 4	ENSP00000542046.1
	FOS	ENST00000944924.1		c.367A>G	p.Ile123Val	missense	Exon 2 of 4	ENSP00000614983.1

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

GnomAD2 exomes AF: 0.00174 AC: 434 AN: 249206 AF XY: 0.00166

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 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

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.00217 AC: 97 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000383 AC: 10 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000429 AC: 37 AN: 86256

European-Finnish (FIN) AF: 0.000714 AC: 38 AN: 53226

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00259 AC: 2885 AN: 1111998

Other (OTH) AF: 0.00182 AC: 110 AN: 60388

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

African (AFR) AF: 0.000361 AC: 15 AN: 41578

American (AMR) AF: 0.00137 AC: 21 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00238 AC: 162 AN: 68016

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00236 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

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-0.99	T
PhyloP100		1.3
PROVEAN	Benign	1.3	N
REVEL	Uncertain	0.34
Sift	Benign	0.17	T
Sift4G	Benign	0.48	T
MVP		0.93
ClinPred		0.057	T
GERP RS		6.0
PromoterAI		-0.023	Neutral
Varity_R		0.096
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs150427794; hg19: chr14-75746805; COSMIC: COSV107328663; COSMIC: COSV107328663;