rs708905

Variant names:

• chr19-45474214-G-C
• rs708905
• NM_006732.3:c.*1202G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006732.3(FOSB):​c.*1202G>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 0.145 in 151,988 control chromosomes in the GnomAD database, including 1,832 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 0.14 (1831 hom., cov: 30)
  • Exomes 𝑓: 0.11 (1 hom.)
• Consequence: FOSB NM_006732.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.13
• Publications: 11 publications found

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]

ERCC1 Gene-Disease associations (from GenCC):

• cerebrooculofacioskeletal syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, G2P
• Cockayne syndrome type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• COFS syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.224 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOSB	NM_006732.3	c.*1202G>C		3_prime_UTR_variant	Exon 4 of 4	ENST00000353609.8	NP_006723.2
FOSB	NM_001114171.2	c.*1202G>C		3_prime_UTR_variant	Exon 3 of 3		NP_001107643.1
FOSB	NM_001411069.1	c.*1365G>C		3_prime_UTR_variant	Exon 5 of 5		NP_001397998.1
FOSB	XM_047438550.1	c.*1365G>C		3_prime_UTR_variant	Exon 4 of 4		XP_047294506.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOSB	ENST00000353609.8	c.*1202G>C		3_prime_UTR_variant	Exon 4 of 4	1	NM_006732.3	ENSP00000245919.3

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22001 AN: 151760 Hom.: 1834 Cov.: 30

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.119

Gnomad AMR AF: 0.0951

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.0507

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.0699

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.125

Gnomad OTH AF: 0.135

GnomAD4 exome AF: 0.109 AC: 12 AN: 110 Hom.: 1 Cov.: 0 AF XY: 0.125 AC XY: 9 AN XY: 72

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AF: 0.102 AC: 10 AN: 98

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.250 AC: 1 AN: 4

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.145 AC: 21999 AN: 151878 Hom.: 1831 Cov.: 30 AF XY: 0.140 AC XY: 10389 AN XY: 74228

African (AFR) AF: 0.228 AC: 9440 AN: 41390

American (AMR) AF: 0.0950 AC: 1450 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 389 AN: 3468

East Asian (EAS) AF: 0.0502 AC: 258 AN: 5138

South Asian (SAS) AF: 0.172 AC: 823 AN: 4796

European-Finnish (FIN) AF: 0.0699 AC: 740 AN: 10584

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.125 AC: 8483 AN: 67932

Other (OTH) AF: 0.134 AC: 282 AN: 2110

Alfa AF: 0.132 Hom.: 182

Bravo AF: 0.146

Asia WGS AF: 0.117 AC: 409 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.6
DANN	Benign	0.60
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs708905; hg19: chr19-45977472;