19-45471335-T-C

Variant names:

• chr19-45471335-T-C
• rs2276469
• ENST00000590335.1:c.*299T>C

Variant summary

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

The ENST00000590335.1(FOSB):​c.*299T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.489 in 1,442,792 control chromosomes in the GnomAD database, including 176,662 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 0.54 (22959 hom., cov: 31)
  • Exomes 𝑓: 0.48 (153703 hom.)
• Consequence: FOSB ENST00000590335.1 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.23
• Publications: 19 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=-0.74).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.686 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000590335.1. 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.555+34T>C		intron	N/A	NP_006723.2	P53539-1
	FOSB	NM_001114171.2		c.447+386T>C		intron	N/A	NP_001107643.1	P53539-2
	FOSB	NM_001411069.1		c.555+34T>C		intron	N/A	NP_001397998.1	P53539-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOSB	ENST00000590335.1	TSL:1	c.*299T>C		3_prime_UTR	Exon 2 of 2	ENSP00000465068.1	K7EJ89
	FOSB	ENST00000353609.8	TSL:1 MANE Select	c.555+34T>C		intron	N/A	ENSP00000245919.3	P53539-1
	FOSB	ENST00000417353.6	TSL:1	c.447+386T>C		intron	N/A	ENSP00000407207.1	P53539-2

Frequencies

GnomAD3 genomes AF: 0.539 AC: 81763 AN: 151674 Hom.: 22926 Cov.: 31

Gnomad AFR AF: 0.692

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.508

Gnomad ASJ AF: 0.437

Gnomad EAS AF: 0.644

Gnomad SAS AF: 0.676

Gnomad FIN AF: 0.439

Gnomad MID AF: 0.503

Gnomad NFE AF: 0.458

Gnomad OTH AF: 0.533

GnomAD2 exomes AF: 0.527 AC: 80542 AN: 152874 AF XY: 0.532

Gnomad AFR exome AF: 0.701

Gnomad AMR exome AF: 0.524

Gnomad ASJ exome AF: 0.444

Gnomad EAS exome AF: 0.639

Gnomad FIN exome AF: 0.439

Gnomad NFE exome AF: 0.460

Gnomad OTH exome AF: 0.504

GnomAD4 exome AF: 0.483 AC: 623647 AN: 1291000 Hom.: 153703 Cov.: 19 AF XY: 0.488 AC XY: 312954 AN XY: 641100

African (AFR) AF: 0.696 AC: 20621 AN: 29626

American (AMR) AF: 0.520 AC: 18488 AN: 35542

Ashkenazi Jewish (ASJ) AF: 0.441 AC: 10785 AN: 24448

East Asian (EAS) AF: 0.633 AC: 22282 AN: 35224

South Asian (SAS) AF: 0.669 AC: 51546 AN: 77036

European-Finnish (FIN) AF: 0.443 AC: 21342 AN: 48146

Middle Eastern (MID) AF: 0.528 AC: 2847 AN: 5390

European-Non Finnish (NFE) AF: 0.457 AC: 447955 AN: 981130

Other (OTH) AF: 0.510 AC: 27781 AN: 54458

GnomAD4 genome AF: 0.539 AC: 81843 AN: 151792 Hom.: 22959 Cov.: 31 AF XY: 0.542 AC XY: 40188 AN XY: 74182

African (AFR) AF: 0.693 AC: 28663 AN: 41380

American (AMR) AF: 0.508 AC: 7744 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.437 AC: 1516 AN: 3472

East Asian (EAS) AF: 0.643 AC: 3300 AN: 5132

South Asian (SAS) AF: 0.675 AC: 3255 AN: 4822

European-Finnish (FIN) AF: 0.439 AC: 4631 AN: 10544

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.458 AC: 31065 AN: 67880

Other (OTH) AF: 0.534 AC: 1125 AN: 2108

Alfa AF: 0.499 Hom.: 50447

Bravo AF: 0.549

Asia WGS AF: 0.654 AC: 2276 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.91
DANN	Benign	0.75
PhyloP100		-2.2
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: rs2276469; hg19: chr19-45974593; COSMIC: COSV62278461;