rs2238686

Variant names:

• chr19-45469798-T-C
• rs2238686
• NM_006732.3:c.127-831T>C

Variant summary

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

The NM_006732.3(FOSB):​c.127-831T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 152,350 control chromosomes in the GnomAD database, including 1,881 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 (1879 hom., cov: 32)
  • Exomes 𝑓: 0.11 (2 hom.)
• Consequence: FOSB NM_006732.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.67
• Publications: 15 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOSB	NM_006732.3	c.127-831T>C		intron_variant	Intron 1 of 3	ENST00000353609.8	NP_006723.2
FOSB	NM_001114171.2	c.127-831T>C		intron_variant	Intron 1 of 2		NP_001107643.1
FOSB	NM_001411069.1	c.127-831T>C		intron_variant	Intron 1 of 4		NP_001397998.1
FOSB	XM_047438550.1	c.127-831T>C		intron_variant	Intron 1 of 3		XP_047294506.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOSB	ENST00000353609.8	c.127-831T>C		intron_variant	Intron 1 of 3	1	NM_006732.3	ENSP00000245919.3

Frequencies

GnomAD3 genomes AF: 0.137 AC: 20875 AN: 151986 Hom.: 1874 Cov.: 32

Gnomad AFR AF: 0.0908

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.244

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.402

Gnomad SAS AF: 0.253

Gnomad FIN AF: 0.0942

Gnomad MID AF: 0.182

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.144

GnomAD4 exome AF: 0.111 AC: 27 AN: 244 Hom.: 2 AF XY: 0.136 AC XY: 25 AN XY: 184

African (AFR) AF: 0.00 AC: 0 AN: 6

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.167 AC: 1 AN: 6

South Asian (SAS) AF: 0.375 AC: 3 AN: 8

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 12

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.113 AC: 23 AN: 204

Other (OTH) AF: 0.00 AC: 0 AN: 6

GnomAD4 genome AF: 0.137 AC: 20893 AN: 152106 Hom.: 1879 Cov.: 32 AF XY: 0.144 AC XY: 10728 AN XY: 74344

African (AFR) AF: 0.0907 AC: 3767 AN: 41524

American (AMR) AF: 0.245 AC: 3736 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 576 AN: 3468

East Asian (EAS) AF: 0.402 AC: 2076 AN: 5164

South Asian (SAS) AF: 0.251 AC: 1206 AN: 4796

European-Finnish (FIN) AF: 0.0942 AC: 999 AN: 10606

Middle Eastern (MID) AF: 0.182 AC: 53 AN: 292

European-Non Finnish (NFE) AF: 0.118 AC: 8030 AN: 67954

Other (OTH) AF: 0.149 AC: 316 AN: 2114

Alfa AF: 0.129 Hom.: 784

Bravo AF: 0.151

Asia WGS AF: 0.323 AC: 1122 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	15
DANN	Benign	0.84
PhyloP100		1.7
PromoterAI		0.077	Neutral
Mutation Taster		=98/2	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: rs2238686; hg19: chr19-45973056;