19-45475117-A-G

Variant names:

• chr19-45475117-A-G
• rs1049739
• NM_006732.3:c.*2105A>G

Variant summary

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

The NM_006732.3(FOSB):​c.*2105A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.468 in 152,466 control chromosomes in the GnomAD database, including 18,026 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 0.47 (17998 hom., cov: 31)
  • Exomes 𝑓: 0.38 (28 hom.)
• Consequence: FOSB NM_006732.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.736
• Publications: 13 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=-0.73).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.655 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOSB	NM_006732.3	c.*2105A>G		3_prime_UTR_variant	Exon 4 of 4	ENST00000353609.8	NP_006723.2
FOSB	NM_001114171.2	c.*2105A>G		3_prime_UTR_variant	Exon 3 of 3		NP_001107643.1
FOSB	NM_001411069.1	c.*2268A>G		3_prime_UTR_variant	Exon 5 of 5		NP_001397998.1
FOSB	XM_047438550.1	c.*2268A>G		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.*2105A>G		3_prime_UTR_variant	Exon 4 of 4	1	NM_006732.3	ENSP00000245919.3

Frequencies

GnomAD3 genomes AF: 0.468 AC: 71164 AN: 151906 Hom.: 17961 Cov.: 31

Gnomad AFR AF: 0.661

Gnomad AMI AF: 0.290

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.306

Gnomad EAS AF: 0.336

Gnomad SAS AF: 0.557

Gnomad FIN AF: 0.373

Gnomad MID AF: 0.392

Gnomad NFE AF: 0.406

Gnomad OTH AF: 0.449

GnomAD4 exome AF: 0.376 AC: 166 AN: 442 Hom.: 28 Cov.: 0 AF XY: 0.380 AC XY: 101 AN XY: 266

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.373 AC: 152 AN: 408

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.385 AC: 10 AN: 26

Other (OTH) AF: 0.667 AC: 4 AN: 6

GnomAD4 genome AF: 0.469 AC: 71250 AN: 152024 Hom.: 17998 Cov.: 31 AF XY: 0.465 AC XY: 34547 AN XY: 74314

African (AFR) AF: 0.662 AC: 27435 AN: 41468

American (AMR) AF: 0.358 AC: 5464 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.306 AC: 1062 AN: 3466

East Asian (EAS) AF: 0.335 AC: 1735 AN: 5174

South Asian (SAS) AF: 0.557 AC: 2688 AN: 4824

European-Finnish (FIN) AF: 0.373 AC: 3941 AN: 10558

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.406 AC: 27592 AN: 67956

Other (OTH) AF: 0.452 AC: 952 AN: 2108

Alfa AF: 0.435 Hom.: 25483

Bravo AF: 0.472

Asia WGS AF: 0.484 AC: 1686 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	2.0
DANN	Benign	0.64
PhyloP100		-0.74
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: rs1049739; hg19: chr19-45978375;