14-75280415-G-T

Variant names:

• chr14-75280415-G-T
• rs1063169
• NM_005252.4:c.394-145G>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_005252.4(FOS):​c.394-145G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 709,386 control chromosomes in the GnomAD database, including 8,808 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 0.12 (1449 hom., cov: 33)
  • Exomes 𝑓: 0.16 (7359 hom.)
• Consequence: FOS NM_005252.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.10
• Publications: 31 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 (BayesDel_noAF=-0.38).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOS	NM_005252.4	MANE Select	c.394-145G>T		intron	N/A	NP_005243.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOS	ENST00000303562.9	TSL:1 MANE Select	c.394-145G>T		intron	N/A	ENSP00000306245.4
	FOS	ENST00000555347.1	TSL:2	c.-196G>T		5_prime_UTR	Exon 1 of 2	ENSP00000450886.1
	FOS	ENST00000535987.6	TSL:2	c.393+287G>T		intron	N/A	ENSP00000442268.1

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18032 AN: 152092 Hom.: 1438 Cov.: 33

Gnomad AFR AF: 0.0281

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.0859

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.229

Gnomad SAS AF: 0.0957

Gnomad FIN AF: 0.163

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.103

GnomAD4 exome AF: 0.156 AC: 87108 AN: 557176 Hom.: 7359 Cov.: 7 AF XY: 0.154 AC XY: 44854 AN XY: 291550

African (AFR) AF: 0.0264 AC: 376 AN: 14222

American (AMR) AF: 0.0831 AC: 1736 AN: 20880

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 1775 AN: 14774

East Asian (EAS) AF: 0.254 AC: 8097 AN: 31820

South Asian (SAS) AF: 0.0984 AC: 4809 AN: 48870

European-Finnish (FIN) AF: 0.169 AC: 7524 AN: 44536

Middle Eastern (MID) AF: 0.0988 AC: 256 AN: 2592

European-Non Finnish (NFE) AF: 0.167 AC: 58428 AN: 350062

Other (OTH) AF: 0.140 AC: 4107 AN: 29420

GnomAD4 genome AF: 0.119 AC: 18052 AN: 152210 Hom.: 1449 Cov.: 33 AF XY: 0.117 AC XY: 8734 AN XY: 74398

African (AFR) AF: 0.0280 AC: 1163 AN: 41542

American (AMR) AF: 0.0859 AC: 1315 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 387 AN: 3472

East Asian (EAS) AF: 0.230 AC: 1189 AN: 5176

South Asian (SAS) AF: 0.0959 AC: 463 AN: 4826

European-Finnish (FIN) AF: 0.163 AC: 1724 AN: 10588

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.168 AC: 11448 AN: 67986

Other (OTH) AF: 0.112 AC: 236 AN: 2114

Alfa AF: 0.146 Hom.: 5690

Bravo AF: 0.109

Asia WGS AF: 0.164 AC: 569 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	14
DANN	Benign	0.88
PhyloP100		1.1
PromoterAI		-0.036	Neutral
Mutation Taster		=299/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1063169; hg19: chr14-75747118;