19-9811408-C-G

Variant names:

• chr19-9811408-C-G
• rs61753275
• NM_017703.3:c.469G>C

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.469G>C​(p.Val157Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 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. V157M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FBXL12 NM_017703.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.404
• Publications: 0 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=0.16445488).

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.469G>C	p.Val157Leu	missense	Exon 3 of 3	NP_060173.1	Q9NXK8-1
	FBXL12	NM_001316936.2		c.370G>C	p.Val124Leu	missense	Exon 2 of 2	NP_001303865.1
	FBXL12	NM_001316937.2		c.310G>C	p.Val104Leu	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.469G>C	p.Val157Leu	missense	Exon 3 of 3	ENSP00000247977.3	Q9NXK8-1
	FBXL12	ENST00000591009.1	TSL:1	c.310G>C	p.Val104Leu	missense	Exon 2 of 2	ENSP00000468369.1	Q9NXK8-2
	FBXL12	ENST00000586651.5	TSL:1	c.*321G>C		3_prime_UTR	Exon 2 of 2	ENSP00000467059.1	K7EPT3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460978 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 726824

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

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52608

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111960

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	22
DANN	Benign	0.92
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.40
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.052
Sift	Benign	0.54	T
Sift4G	Benign	0.33	T
Polyphen		0.69	P
Vest4		0.093
MutPred		0.50		Loss of catalytic residue at V157 (P = 0.0103)
MVP		0.24
MPC		0.50
ClinPred		0.36	T
GERP RS		2.6
Varity_R		0.037
gMVP		0.54
Mutation Taster		=96/4	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: rs61753275; hg19: chr19-9922084; COSMIC: COSV104558390; COSMIC: COSV104558390;