10-102421467-A-T

Variant names:

• chr10-102421467-A-T
• rs1430802250
• NM_024326.4:c.167A>T

Variant summary

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

The NM_024326.4(FBXL15):​c.167A>T​(p.Gln56Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000462 in 1,514,278 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: FBXL15 NM_024326.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.25
• Publications: 0 publications found

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]

PSD (HGNC:9507): (pleckstrin and Sec7 domain containing) This gene encodes a Plekstrin homology and SEC7 domains-containing protein that functions as a guanine nucleotide exchange factor. The encoded protein regulates signal transduction by activating ADP-ribosylation factor 6. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024326.4. 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
	FBXL15	NM_024326.4	MANE Select	c.167A>T	p.Gln56Leu	missense	Exon 2 of 4	NP_077302.3
	FBXL15	NM_001387294.1		c.167A>T	p.Gln56Leu	missense	Exon 3 of 5	NP_001374223.1	Q9H469

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXL15	ENST00000369956.8	TSL:1 MANE Select	c.167A>T	p.Gln56Leu	missense	Exon 2 of 4	ENSP00000358972.3	Q9H469
	FBXL15	ENST00000864349.1		c.167A>T	p.Gln56Leu	missense	Exon 3 of 5	ENSP00000534408.1
	FBXL15	ENST00000864350.1		c.167A>T	p.Gln56Leu	missense	Exon 3 of 5	ENSP00000534409.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00000147 AC: 2 AN: 1362104 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 670170

African (AFR) AF: 0.0000327 AC: 1 AN: 30602

American (AMR) AF: 0.00 AC: 0 AN: 31702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23600

East Asian (EAS) AF: 0.00 AC: 0 AN: 35440

South Asian (SAS) AF: 0.00 AC: 0 AN: 76286

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36130

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5102

European-Non Finnish (NFE) AF: 9.38e-7 AC: 1 AN: 1066568

Other (OTH) AF: 0.00 AC: 0 AN: 56674

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152174 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74338

African (AFR) AF: 0.0000724 AC: 3 AN: 41454

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

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: 68010

Other (OTH) AF: 0.000478 AC: 1 AN: 2094

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	0.15
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	24
DANN	Benign	0.91
DEOGEN2	Benign	0.084	T
Eigen	Benign	0.035
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		7.2
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.24
Sift	Benign	0.034	D
Sift4G	Uncertain	0.031	D
Polyphen		0.19	B
Vest4		0.61
MutPred		0.55		Gain of stability (P = 0.0197)
MVP		0.44
MPC		1.2
ClinPred		0.93	D
GERP RS		5.2
Varity_R		0.74
gMVP		0.57
Mutation Taster		=62/38	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: rs1430802250; hg19: chr10-104181224;