rs2238687

Variant names:

• chr19-45469908-G-C
• rs2238687
• NM_006732.3:c.127-721G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-45469908-G-C
• chr19-45469908-G-T

Variant summary

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

The NM_006732.3(FOSB):​c.127-721G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 151,986 control chromosomes in the GnomAD database, including 1,989 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 0.15 (1987 hom., cov: 31)
  • Exomes 𝑓: 0.099 (2 hom.)
• Consequence: FOSB NM_006732.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.39
• Publications: 12 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• 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=-0.69).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006732.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOSB	NM_006732.3	MANE Select	c.127-721G>C		intron	N/A	NP_006723.2	P53539-1
	FOSB	NM_001114171.2		c.127-721G>C		intron	N/A	NP_001107643.1	P53539-2
	FOSB	NM_001411069.1		c.127-721G>C		intron	N/A	NP_001397998.1	P53539-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOSB	ENST00000353609.8	TSL:1 MANE Select	c.127-721G>C		intron	N/A	ENSP00000245919.3	P53539-1
	FOSB	ENST00000417353.6	TSL:1	c.127-721G>C		intron	N/A	ENSP00000407207.1	P53539-2
	FOSB	ENST00000591858.5	TSL:1	c.127-838G>C		intron	N/A	ENSP00000466530.1	P53539-3

Frequencies

GnomAD3 genomes AF: 0.145 AC: 21999 AN: 151676 Hom.: 1982 Cov.: 31

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.147

Gnomad AMR AF: 0.246

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.403

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.0946

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.147

GnomAD4 exome AF: 0.0990 AC: 19 AN: 192 Hom.: 2 Cov.: 0 AF XY: 0.0972 AC XY: 14 AN XY: 144

African (AFR) AF: 0.00 AC: 0 AN: 8

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4

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

South Asian (SAS) AF: 0.125 AC: 1 AN: 8

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.112 AC: 17 AN: 152

Other (OTH) AF: 0.167 AC: 1 AN: 6

GnomAD4 genome AF: 0.145 AC: 22024 AN: 151794 Hom.: 1987 Cov.: 31 AF XY: 0.152 AC XY: 11256 AN XY: 74134

African (AFR) AF: 0.118 AC: 4877 AN: 41352

American (AMR) AF: 0.247 AC: 3762 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 576 AN: 3472

East Asian (EAS) AF: 0.403 AC: 2053 AN: 5100

South Asian (SAS) AF: 0.253 AC: 1214 AN: 4804

European-Finnish (FIN) AF: 0.0946 AC: 998 AN: 10552

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.118 AC: 8035 AN: 67960

Other (OTH) AF: 0.152 AC: 322 AN: 2112

Alfa AF: 0.0502 Hom.: 39

Bravo AF: 0.160

Asia WGS AF: 0.325 AC: 1130 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	16
DANN	Benign	0.81
PhyloP100		1.4
PromoterAI		-0.038	Neutral
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: rs2238687; hg19: chr19-45973166;