19-45468683-G-A

Variant names:

• chr19-45468683-G-A
• rs28381241
• NM_006732.3:c.97G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006732.3(FOSB):​c.97G>A​(p.Gly33Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000878 in 1,611,072 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0048 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00047 (8 hom.)
• Consequence: FOSB NM_006732.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.77
• Publications: 2 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

ENSG00000299344 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0075651407).
• BP6: Variant 19-45468683-G-A is Benign according to our data. Variant chr19-45468683-G-A is described in ClinVar as Benign. ClinVar VariationId is 785628.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00475 (723/152124) while in subpopulation AFR AF = 0.0168 (698/41498). AF 95% confidence interval is 0.0158. There are 2 homozygotes in GnomAd4. There are 333 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 723 AD gene.

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.97G>A	p.Gly33Ser	missense	Exon 1 of 4	NP_006723.2	P53539-1
	FOSB	NM_001114171.2		c.97G>A	p.Gly33Ser	missense	Exon 1 of 3	NP_001107643.1	P53539-2
	FOSB	NM_001411069.1		c.97G>A	p.Gly33Ser	missense	Exon 1 of 5	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.97G>A	p.Gly33Ser	missense	Exon 1 of 4	ENSP00000245919.3	P53539-1
	FOSB	ENST00000417353.6	TSL:1	c.97G>A	p.Gly33Ser	missense	Exon 1 of 3	ENSP00000407207.1	P53539-2
	FOSB	ENST00000591858.5	TSL:1	c.97G>A	p.Gly33Ser	missense	Exon 1 of 4	ENSP00000466530.1	P53539-3

Frequencies

GnomAD3 genomes AF: 0.00472 AC: 718 AN: 152008 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.0167

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00123 AC: 303 AN: 246716 AF XY: 0.000947

Gnomad AFR exome AF: 0.0175

Gnomad AMR exome AF: 0.000718

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000892

Gnomad OTH exome AF: 0.000497

GnomAD4 exome AF: 0.000474 AC: 691 AN: 1458948 Hom.: 8 Cov.: 30 AF XY: 0.000416 AC XY: 302 AN XY: 725850

African (AFR) AF: 0.0178 AC: 593 AN: 33236

American (AMR) AF: 0.000730 AC: 32 AN: 43858

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26028

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39558

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.000355 AC: 2 AN: 5634

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111130

Other (OTH) AF: 0.000979 AC: 59 AN: 60284

GnomAD4 genome AF: 0.00475 AC: 723 AN: 152124 Hom.: 2 Cov.: 31 AF XY: 0.00448 AC XY: 333 AN XY: 74358

African (AFR) AF: 0.0168 AC: 698 AN: 41498

American (AMR) AF: 0.00111 AC: 17 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68002

Other (OTH) AF: 0.00238 AC: 5 AN: 2104

Alfa AF: 0.00133 Hom.: 7

Bravo AF: 0.00555

ESP6500AA AF: 0.0177 AC: 78

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00155 AC: 188

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0076	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.0	L
PhyloP100		3.8
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.23
Sift	Benign	0.97	T
Sift4G	Benign	0.53	T
Polyphen		1.0	D
Vest4		0.27
MVP		0.37
MPC		1.7
ClinPred		0.025	T
GERP RS		5.4
PromoterAI		-0.013	Neutral
Varity_R		0.23
gMVP		0.31
Mutation Taster		=68/32	polymorphism

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: rs28381241; hg19: chr19-45971941;