19-45468683-G-A

Position:

• chr19-45468683-G-A

Variant summary

Our verdict is Benign. Variant got -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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 723 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FOSB	NM_006732.3	c.97G>A	p.Gly33Ser	missense_variant	1/4	ENST00000353609.8
FOSB	NM_001114171.2	c.97G>A	p.Gly33Ser	missense_variant	1/3
FOSB	NM_001411069.1	c.97G>A	p.Gly33Ser	missense_variant	1/5
FOSB	XM_047438550.1	c.97G>A	p.Gly33Ser	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FOSB	ENST00000353609.8	c.97G>A	p.Gly33Ser	missense_variant	1/4	1	NM_006732.3	P1

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

GnomAD3 exomes AF: 0.00123 AC: 303 AN: 246716 Hom.: 3 AF XY: 0.000947 AC XY: 127 AN XY: 134038

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 SAS 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

Gnomad4 AFR exome AF: 0.0178

Gnomad4 AMR exome AF: 0.000730

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000979

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

Gnomad4 AFR AF: 0.0168

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00238

Alfa AF: 0.000860 Hom.: 0

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

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0076	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.0	L;L;L;L;L;L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.67	T
Sift4G	Benign	0.53	T;T;T;T;T;T;T;T
Polyphen		1.0	.;.;.;D;.;.;.;.
Vest4		0.27
MVP		0.37
MPC		1.7
ClinPred		0.025	T
GERP RS		5.4
Varity_R		0.23
gMVP		0.31

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

Publications

LitVar

Other links and lift over

dbSNP: rs28381241; hg19: chr19-45971941;