rs991654454

Variant names:

• chr11-65896925-G-T
• rs991654454
• NM_005438.5:c.181C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005438.5(FOSL1):​c.181C>A​(p.Pro61Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,613,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FOSL1 NM_005438.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.07
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19575348).

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.181C>A	p.Pro61Thr	missense	Exon 2 of 4	NP_005429.1	A0A0S2Z595
	FOSL1	NM_001300844.2		c.181C>A	p.Pro61Thr	missense	Exon 2 of 3	NP_001287773.1	E9PPX2
	FOSL1	NM_001300855.2		c.181C>A	p.Pro61Thr	missense	Exon 2 of 4	NP_001287784.1	E9PKL5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FOSL1	ENST00000312562.7	TSL:1 MANE Select	c.181C>A	p.Pro61Thr	missense	Exon 2 of 4	ENSP00000310170.2	P15407-1
	FOSL1	ENST00000531493.5	TSL:1	c.181C>A	p.Pro61Thr	missense	Exon 2 of 3	ENSP00000436276.1	E9PPX2
	FOSL1	ENST00000913992.1		c.178C>A	p.Pro60Thr	missense	Exon 2 of 4	ENSP00000584051.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000478

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461610 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727126

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111744

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74344

African (AFR) AF: 0.00 AC: 0 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

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	Benign	0.077
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.1
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.57	N
REVEL	Uncertain	0.34
Sift	Benign	0.10	T
Sift4G	Benign	0.15	T
Polyphen		0.82	P
Vest4		0.25
MutPred		0.34		Gain of catalytic residue at P61 (P = 0.0187)
MVP		0.89
MPC		0.11
ClinPred		0.66	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.16
gMVP		0.56
Mutation Taster		=64/36	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: rs991654454; hg19: chr11-65664396;