8-144355646-T-C

Variant names:

• chr8-144355646-T-C
• NM_012162.4:c.1505A>G

Variant summary

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

The NM_012162.4(FBXL6):​c.1505A>G​(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 (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FBXL6 NM_012162.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.16
• Publications: 0 publications found

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]

SLC52A2 Gene-Disease associations (from GenCC):

• Brown-Vialetto-van Laere syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P

ENSG00000271698 (HGNC:):

ACMG classification

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

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXL6	NM_012162.4	c.1505A>G	p.Tyr502Cys	missense_variant	Exon 9 of 9	ENST00000331890.6	NP_036294.2
FBXL6	NM_024555.6	c.1487A>G	p.Tyr496Cys	missense_variant	Exon 9 of 9		NP_078831.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXL6	ENST00000331890.6	c.1505A>G	p.Tyr502Cys	missense_variant	Exon 9 of 9	1	NM_012162.4	ENSP00000330098.5
ENSG00000271698	ENST00000531225.1	n.-38A>G		upstream_gene_variant		2		ENSP00000436572.2

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

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4414

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111786

Other (OTH) AF: 0.00 AC: 0 AN: 60184

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 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
PhyloP100		3.2
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
Mutation Taster		=73/27	polymorphism

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

Other links and lift over

hg19: chr8-145579306; COSMIC: COSV57351200; COSMIC: COSV57351200;