rs28381252

Positions:

• chr19-45473246-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_006732.3(FOSB):​c.*234T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00244 in 485,236 control chromosomes in the GnomAD database, including 21 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 0.0015 (8 hom., cov: 31)
  • Exomes 𝑓: 0.0029 (13 hom.)
• Consequence: FOSB NM_006732.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00700

Genes affected

FOSB (HGNC:3797): (FosB 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. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ERCC1 (HGNC:3433): (ERCC excision repair 1, endonuclease non-catalytic subunit) The product of this gene functions in the nucleotide excision repair pathway, and is required for the repair of DNA lesions such as those induced by UV light or formed by electrophilic compounds including cisplatin. The encoded protein forms a heterodimer with the XPF endonuclease (also known as ERCC4), and the heterodimeric endonuclease catalyzes the 5' incision in the process of excising the DNA lesion. The heterodimeric endonuclease is also involved in recombinational DNA repair and in the repair of inter-strand crosslinks. Mutations in this gene result in cerebrooculofacioskeletal syndrome, and polymorphisms that alter expression of this gene may play a role in carcinogenesis. Multiple transcript variants encoding different isoforms have been found for this gene. The last exon of this gene overlaps with the CD3e molecule, epsilon associated protein gene on the opposite strand. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00152 (228/149924) while in subpopulation EAS AF= 0.038 (189/4980). AF 95% confidence interval is 0.0335. There are 8 homozygotes in gnomad4. There are 131 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 228 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FOSB	NM_006732.3	c.*234T>C		3_prime_UTR_variant	4/4	ENST00000353609.8	NP_006723.2
FOSB	NM_001114171.2	c.*234T>C		3_prime_UTR_variant	3/3		NP_001107643.1
FOSB	NM_001411069.1	c.*397T>C		3_prime_UTR_variant	5/5		NP_001397998.1
FOSB	XM_047438550.1	c.*397T>C		3_prime_UTR_variant	4/4		XP_047294506.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FOSB	ENST00000353609.8	c.*234T>C		3_prime_UTR_variant	4/4	1	NM_006732.3	ENSP00000245919.3

Frequencies

GnomAD3 genomes AF: 0.00153 AC: 229 AN: 149808 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.000195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000464

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0383

Gnomad SAS AF: 0.00321

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000446

Gnomad OTH AF: 0.00243

GnomAD4 exome AF: 0.00285 AC: 957 AN: 335312 Hom.: 13 Cov.: 4 AF XY: 0.00274 AC XY: 487 AN XY: 177438

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0399

Gnomad4 SAS exome AF: 0.000956

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000344

Gnomad4 OTH exome AF: 0.00385

GnomAD4 genome AF: 0.00152 AC: 228 AN: 149924 Hom.: 8 Cov.: 31 AF XY: 0.00179 AC XY: 131 AN XY: 73186

Gnomad4 AFR AF: 0.000195

Gnomad4 AMR AF: 0.000463

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0380

Gnomad4 SAS AF: 0.00321

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000446

Gnomad4 OTH AF: 0.00288

Alfa AF: 0.000630 Hom.: 0

Bravo AF: 0.00141

Asia WGS AF: 0.0250 AC: 85 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	16
DANN	Benign	0.71

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: rs28381252; hg19: chr19-45976504; COSMIC: COSV62278590; COSMIC: COSV62278590;