chr19-45470722-A-C

Variant names:

• chr19-45470722-A-C
• rs780193148
• NM_006732.3:c.220A>C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_006732.3(FOSB):​c.220A>C​(p.Thr74Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,540 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T74A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: FOSB NM_006732.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.50

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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FOSB	NM_006732.3	c.220A>C	p.Thr74Pro	missense_variant	Exon 2 of 4	ENST00000353609.8	NP_006723.2
FOSB	NM_001114171.2	c.220A>C	p.Thr74Pro	missense_variant	Exon 2 of 3		NP_001107643.1
FOSB	NM_001411069.1	c.220A>C	p.Thr74Pro	missense_variant	Exon 2 of 5		NP_001397998.1
FOSB	XM_047438550.1	c.220A>C	p.Thr74Pro	missense_variant	Exon 2 of 4		XP_047294506.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FOSB	ENST00000353609.8	c.220A>C	p.Thr74Pro	missense_variant	Exon 2 of 4	1	NM_006732.3	ENSP00000245919.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460540 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 726682

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000115

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000577 AC: 7

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	.;.;D;.;T;.;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.78	T;D;T;T;T;T;T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.70	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	2.0	M;M;M;.;.;.;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.7	.;D;D;.;.;.;.;.
REVEL	Uncertain	0.52
Sift	Uncertain	0.015	.;D;D;.;.;.;.;.
Sift4G	Uncertain	0.011	D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;D;.;.;.;.;.
Vest4		0.66
MutPred		0.48		Gain of catalytic residue at P73 (P = 0.0112);Gain of catalytic residue at P73 (P = 0.0112);Gain of catalytic residue at P73 (P = 0.0112);Gain of catalytic residue at P73 (P = 0.0112);Gain of catalytic residue at P73 (P = 0.0112);.;.;.;
MVP		0.55
MPC		1.6
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.79
gMVP		0.62

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: rs780193148; hg19: chr19-45973980; COSMIC: COSV62278361; COSMIC: COSV62278361;