8-144355538-G-C

Position:

• chr8-144355538-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012162.4(FBXL6):​c.1613C>G​(p.Pro538Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000755 in 1,456,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: FBXL6 NM_012162.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.408

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]

ENSG00000271698 (HGNC:):

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08054432).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXL6	NM_012162.4	c.1613C>G	p.Pro538Arg	missense_variant	9/9	ENST00000331890.6	NP_036294.2
FBXL6	NM_024555.6	c.1595C>G	p.Pro532Arg	missense_variant	9/9		NP_078831.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXL6	ENST00000331890.6	c.1613C>G	p.Pro538Arg	missense_variant	9/9	1	NM_012162.4	ENSP00000330098.5
ENSG00000271698	ENST00000531225.1	n.71C>G		non_coding_transcript_exon_variant	1/6	2		ENSP00000436572.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000806 AC: 2 AN: 248022 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 134934

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000755 AC: 11 AN: 1456940 Hom.: 0 Cov.: 29 AF XY: 0.00000966 AC XY: 7 AN XY: 724304

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000811

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2021

The c.1613C>G (p.P538R) alteration is located in exon 9 (coding exon 9) of the FBXL6 gene. This alteration results from a C to G substitution at nucleotide position 1613, causing the proline (P) at amino acid position 538 to be replaced by an arginine (R). 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	0.073
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	11
DANN	Benign	0.78
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.14	N
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.081	T;T
MetaSVM	Benign	-0.99	T
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.80	N;N
REVEL	Benign	0.017
Sift	Benign	0.32	T;T
Sift4G	Benign	0.079	T;T
Vest4		0.11
MutPred		0.47		.;Loss of glycosylation at P538 (P = 8e-04);
MVP		0.14
MPC		0.064
ClinPred		0.031	T
GERP RS		-0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
gMVP		0.22

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

LitVar

Other links and lift over

dbSNP: rs1344606964; hg19: chr8-145579198;