15-63601352-C-T

Variant names:

• chr15-63601352-C-T
• rs761407354
• ENST00000360587.2:c.410C>T

Variant summary

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

The NM_203373.3(FBXL22):​c.410C>T​(p.Thr137Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. T137S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FBXL22 NM_203373.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0590
• Publications: 0 publications found

Genes affected

FBXL22 (HGNC:27537): (F-box and leucine rich repeat protein 22) This gene encodes a member of the F-box protein family. This F-box protein interacts with S-phase kinase-associated protein 1A and cullin in order to form SCF complexes which function as ubiquitin ligases.[provided by RefSeq, Sep 2010]

USP3-AS1 (HGNC:44140): (USP3 antisense RNA 1)

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=0.07019836).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203373.3. 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
	FBXL22	NM_203373.3		c.410C>T	p.Thr137Ile	missense	Exon 2 of 2	NP_976307.2	Q6P050
	FBXL22	NM_001367809.1		c.*60C>T		3_prime_UTR	Exon 3 of 3	NP_001354738.1	H0YMQ4
	FBXL22	NM_001367807.1	MANE Select	c.*313C>T		downstream_gene	N/A	NP_001354736.1	A0A1W2PQW8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXL22	ENST00000360587.2	TSL:1	c.410C>T	p.Thr137Ile	missense	Exon 2 of 2	ENSP00000353794.3	Q6P050
	FBXL22	ENST00000560325.1	TSL:3	c.*60C>T		3_prime_UTR	Exon 3 of 3	ENSP00000473666.1	R4GNI3
	USP3-AS1	ENST00000561256.5	TSL:3	n.238G>A		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451766 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 722262

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32924

American (AMR) AF: 0.00 AC: 0 AN: 44304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25898

East Asian (EAS) AF: 0.00 AC: 0 AN: 39364

South Asian (SAS) AF: 0.00 AC: 0 AN: 86030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47848

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109512

Other (OTH) AF: 0.0000166 AC: 1 AN: 60138

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.0
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0048	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0081	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		0.059
PrimateAI	Uncertain	0.49	T
REVEL	Benign	0.024
Sift4G	Pathogenic	0.0	D
Vest4		0.060
MVP		0.11
MPC		0.73
ClinPred		0.61	D
GERP RS		-0.89
Varity_R		0.039
gMVP		0.16

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: rs761407354; hg19: chr15-63893551;