chr8-144355646-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_012162.4(FBXL6):ā€‹c.1505A>Gā€‹(p.Tyr502Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,660 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 30)
Exomes š‘“: 6.9e-7 ( 0 hom. )

Consequence

FBXL6
NM_012162.4 missense

Scores

1
6
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.16
Variant links:
Genes affected
FBXL6 (HGNC:13603): (F-box and leucine rich repeat protein 6) This gene encodes a member of a family of proteins that are characterized by an F-box motif. The encoded protein also contains leucine-rich repeats. F-box-containing proteins comprise one of the subunits of the SCF (SKP1-cullin-F-box) complex, which functions in phosphorylation-dependent ubiquitination. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]
SLC52A2 (HGNC:30224): (solute carrier family 52 member 2) This gene encodes a membrane protein which belongs to the riboflavin transporter family. In humans, riboflavin must be obtained by intestinal absorption because it cannot be synthesized by the body. The water-soluble vitamin riboflavin is processed to the coenzymes flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD) which then act as intermediaries in many cellular metabolic reactions. Paralogous members of the riboflavin transporter gene family are located on chromosomes 17 and 20. Unlike other members of this family, this gene has higher expression in brain tissue than small intestine. Alternative splicing of this gene results in multiple transcript variants encoding the same protein. Mutations in this gene have been associated with Brown-Vialetto-Van Laere syndrome 2 - an autosomal recessive progressive neurologic disorder characterized by deafness, bulbar dysfunction, and axial and limb hypotonia. [provided by RefSeq, Jul 2012]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
FBXL6NM_012162.4 linkuse as main transcriptc.1505A>G p.Tyr502Cys missense_variant 9/9 ENST00000331890.6
FBXL6NM_024555.6 linkuse as main transcriptc.1487A>G p.Tyr496Cys missense_variant 9/9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
FBXL6ENST00000331890.6 linkuse as main transcriptc.1505A>G p.Tyr502Cys missense_variant 9/91 NM_012162.4 P2Q8N531-1

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD4 exome
AF:
6.86e-7
AC:
1
AN:
1458660
Hom.:
0
Cov.:
29
AF XY:
0.00000138
AC XY:
1
AN XY:
725642
show subpopulations
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
30

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsOct 16, 2023The c.1505A>G (p.Y502C) alteration is located in exon 9 (coding exon 9) of the FBXL6 gene. This alteration results from a A to G substitution at nucleotide position 1505, causing the tyrosine (Y) at amino acid position 502 to be replaced by a cysteine (C). 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
0.33
BayesDel_addAF
Benign
-0.096
T
BayesDel_noAF
Benign
-0.38
CADD
Uncertain
24
DANN
Uncertain
1.0
Eigen
Uncertain
0.45
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Uncertain
0.90
D
M_CAP
Benign
0.035
D
MetaRNN
Uncertain
0.58
D;D
MetaSVM
Benign
-1.1
T
MutationTaster
Benign
0.98
D;D
PrimateAI
Uncertain
0.69
T
PROVEAN
Benign
-1.9
N;N
REVEL
Benign
0.19
Sift
Benign
0.070
T;T
Sift4G
Pathogenic
0.0
D;D
Vest4
0.61
MutPred
0.52
.;Gain of disorder (P = 0.0353);
MVP
0.36
MPC
0.29
ClinPred
0.87
D
GERP RS
4.9
gMVP
0.58

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: chr8-145579306; COSMIC: COSV57351200; COSMIC: COSV57351200; API