10-102421964-C-G

Variant names:

• chr10-102421964-C-G
• NM_024326.4:c.385C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024326.4(FBXL15):​c.385C>G​(p.Arg129Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,446,562 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: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FBXL15 NM_024326.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.00

Genes affected

FBXL15 (HGNC:28155): (F-box and leucine rich repeat protein 15) Involved in G2/M transition of mitotic cell cycle; cellular protein metabolic process; and positive regulation of BMP signaling pathway. Located in cytoplasm. Part of SCF ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3137697).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXL15	NM_024326.4	c.385C>G	p.Arg129Gly	missense_variant	Exon 3 of 4	ENST00000369956.8	NP_077302.3
FBXL15	NM_001387294.1	c.385C>G	p.Arg129Gly	missense_variant	Exon 4 of 5		NP_001374223.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXL15	ENST00000369956.8	c.385C>G	p.Arg129Gly	missense_variant	Exon 3 of 4	1	NM_024326.4	ENSP00000358972.3
FBXL15	ENST00000440407.5	c.385C>G	p.Arg129Gly	missense_variant	Exon 4 of 4	5		ENSP00000405961.1
FBXL15	ENST00000425536.1	c.385C>G	p.Arg129Gly	missense_variant	Exon 4 of 4	2		ENSP00000403646.1
FBXL15	ENST00000432590.5	c.385C>G	p.Arg129Gly	missense_variant	Exon 4 of 4	2		ENSP00000411435.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1446562 Hom.: 0 Cov.: 31 AF XY: 0.00000278 AC XY: 2 AN XY: 719644

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.385C>G (p.R129G) alteration is located in exon 3 (coding exon 3) of the FBXL15 gene. This alteration results from a C to G substitution at nucleotide position 385, causing the arginine (R) at amino acid position 129 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	25
DANN	Uncertain	0.97
DEOGEN2	Benign	0.026	T;T;.;T;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.86	D;D;D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.31	T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.6	.;M;.;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-2.1	N;N;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.34	T;T;T;T;T
Sift4G	Benign	0.73	T;T;T;T;T
Polyphen		0.98	.;D;.;.;.
Vest4		0.69, 0.69
MutPred		0.52		Gain of catalytic residue at R129 (P = 0.0117);Gain of catalytic residue at R129 (P = 0.0117);.;Gain of catalytic residue at R129 (P = 0.0117);Gain of catalytic residue at R129 (P = 0.0117);
MVP		0.54
MPC		1.7
ClinPred		0.87	D
GERP RS		4.0
Varity_R		0.42
gMVP		0.71

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-104181721;