NM_005438.5:c.683C>A

Variant names:

• chr11-65893019-G-T
• rs141976219
• NM_005438.5:c.683C>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_005438.5(FOSL1):​c.683C>A​(p.Pro228His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,612,294 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FOSL1 NM_005438.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.62
• Publications: 1 publications found

Genes affected

FOSL1 (HGNC:13718): (FOS like 1, 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. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.811
• BS2: High AC in GnomAd4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005438.5. 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
	FOSL1	NM_005438.5	MANE Select	c.683C>A	p.Pro228His	missense	Exon 4 of 4	NP_005429.1	A0A0S2Z595
	FOSL1	NM_001300844.2		c.575C>A	p.Pro192His	missense	Exon 3 of 3	NP_001287773.1	E9PPX2
	FOSL1	NM_001300856.2		c.485C>A	p.Pro162His	missense	Exon 3 of 3	NP_001287785.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOSL1	ENST00000312562.7	TSL:1 MANE Select	c.683C>A	p.Pro228His	missense	Exon 4 of 4	ENSP00000310170.2	P15407-1
	FOSL1	ENST00000531493.5	TSL:1	c.575C>A	p.Pro192His	missense	Exon 3 of 3	ENSP00000436276.1	E9PPX2
	FOSL1	ENST00000913992.1		c.680C>A	p.Pro227His	missense	Exon 4 of 4	ENSP00000584051.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249852 AF XY: 0.00

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460168 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726358

African (AFR) AF: 0.0000598 AC: 2 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26034

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5020

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111556

Other (OTH) AF: 0.0000166 AC: 1 AN: 60280

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74320

African (AFR) AF: 0.0000966 AC: 4 AN: 41422

American (AMR) AF: 0.0000655 AC: 1 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.080	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	2.0	M
PhyloP100		7.6
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.43
MVP		0.88
MPC		0.52
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.63
gMVP		0.48
Mutation Taster		=34/66	disease causing

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: rs141976219; hg19: chr11-65660490;