19-9811326-C-T

Variant names:

• chr19-9811326-C-T
• rs768237975
• NM_017703.3:c.551G>A

Variant summary

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

The NM_017703.3(FBXL12):​c.551G>A​(p.Gly184Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000755 in 1,457,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: FBXL12 NM_017703.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.918
• Publications: 1 publications found

Genes affected

FBXL12 (HGNC:13611): (F-box and leucine rich repeat protein 12) Members of the F-box protein family, such as FBXL12, are characterized by an approximately 40-amino acid F-box motif. SCF complexes, formed by SKP1 (MIM 601434), cullin (see CUL1; MIM 603134), and F-box proteins, act as protein-ubiquitin ligases. F-box proteins interact with SKP1 through the F box, and they interact with ubiquitination targets through other protein interaction domains (Jin et al., 2004 [PubMed 15520277]).[supplied by OMIM, Mar 2008]

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=0.17414665).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017703.3. 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
	FBXL12	NM_017703.3	MANE Select	c.551G>A	p.Gly184Asp	missense	Exon 3 of 3	NP_060173.1	Q9NXK8-1
	FBXL12	NM_001316936.2		c.452G>A	p.Gly151Asp	missense	Exon 2 of 2	NP_001303865.1
	FBXL12	NM_001316937.2		c.392G>A	p.Gly131Asp	missense	Exon 3 of 3	NP_001303866.1	Q9NXK8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXL12	ENST00000247977.9	TSL:1 MANE Select	c.551G>A	p.Gly184Asp	missense	Exon 3 of 3	ENSP00000247977.3	Q9NXK8-1
	FBXL12	ENST00000591009.1	TSL:1	c.392G>A	p.Gly131Asp	missense	Exon 2 of 2	ENSP00000468369.1	Q9NXK8-2
	FBXL12	ENST00000586651.5	TSL:1	c.*403G>A		3_prime_UTR	Exon 2 of 2	ENSP00000467059.1	K7EPT3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000814 AC: 2 AN: 245746 AF XY: 0.0000150

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

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: 0.000165

GnomAD4 exome AF: 0.00000755 AC: 11 AN: 1457052 Hom.: 0 Cov.: 35 AF XY: 0.00000965 AC XY: 7 AN XY: 725120

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

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

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48726

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

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111922

Other (OTH) AF: 0.0000166 AC: 1 AN: 60360

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

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	0.75
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	22
DANN	Uncertain	0.97
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.92
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	0.80	N
REVEL	Benign	0.11
Sift	Benign	0.13	T
Sift4G	Benign	0.31	T
Polyphen		0.79	P
Vest4		0.40
MutPred		0.53		Loss of MoRF binding (P = 0.0658)
MVP		0.35
MPC		0.53
ClinPred		0.14	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.058
gMVP		0.81
Mutation Taster		=88/12	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: rs768237975; hg19: chr19-9922002;