6-98926884-A-T

Variant names:

• chr6-98926884-A-T
• rs34316889
• NM_001278716.2:c.105T>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001278716.2(FBXL4):​c.105T>A​(p.His35Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0293 in 1,614,076 control chromosomes in the GnomAD database, including 775 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H35R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.023 (59 hom., cov: 32)
  • Exomes 𝑓: 0.030 (716 hom.)
• Consequence: FBXL4 NM_001278716.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.159
• Publications: 9 publications found

Genes affected

FBXL4 (HGNC:13601): (F-box and leucine rich repeat protein 4) This gene encodes a member of the F-box protein family, which are characterized by an approximately 40 amino acid motif, the F-box. F-box proteins constitute one subunit of modular E3 ubiquitin ligase complexes, called SCF complexes, which function in phosphorylation-dependent ubiquitination. The F-box domain mediates protein-protein interactions and binds directly to S-phase kinase-associated protein 1. In addition to an F-box domain, the encoded protein contains at least 9 tandem leucine-rich repeats. The ubiquitin ligase complex containing the encoded protein may function in cell-cycle control by regulating levels of lysine-specific demethylase 4A. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

FBXL4 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial DNA depletion syndrome 13

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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 24 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 0.55467 (below the threshold of 3.09). Trascript score misZ: 1.2845 (below the threshold of 3.09). GenCC associations: The gene is linked to Leigh syndrome, mitochondrial DNA depletion syndrome 13.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0030468106).
• BP6: Variant 6-98926884-A-T is Benign according to our data. Variant chr6-98926884-A-T is described in ClinVar as Benign. ClinVar VariationId is 260207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0231 (3510/152230) while in subpopulation NFE AF = 0.0355 (2417/67998). AF 95% confidence interval is 0.0344. There are 59 homozygotes in GnomAd4. There are 1608 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 59 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278716.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXL4	NM_001278716.2	MANE Select	c.105T>A	p.His35Gln	missense	Exon 4 of 10	NP_001265645.1
	FBXL4	NM_012160.5		c.105T>A	p.His35Gln	missense	Exon 3 of 9	NP_036292.2
	FBXL4	NR_103836.2		n.436T>A		non_coding_transcript_exon	Exon 3 of 8

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXL4	ENST00000369244.7	TSL:1 MANE Select	c.105T>A	p.His35Gln	missense	Exon 4 of 10	ENSP00000358247.1
	FBXL4	ENST00000229971.2	TSL:1	c.105T>A	p.His35Gln	missense	Exon 3 of 9	ENSP00000229971.1

Frequencies

GnomAD3 genomes AF: 0.0231 AC: 3510 AN: 152112 Hom.: 59 Cov.: 32

Gnomad AFR AF: 0.00739

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.0265

Gnomad ASJ AF: 0.0505

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00896

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0356

Gnomad OTH AF: 0.0230

GnomAD2 exomes AF: 0.0220 AC: 5523 AN: 251384 AF XY: 0.0225

Gnomad AFR exome AF: 0.00572

Gnomad AMR exome AF: 0.0180

Gnomad ASJ exome AF: 0.0453

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0123

Gnomad NFE exome AF: 0.0333

Gnomad OTH exome AF: 0.0256

GnomAD4 exome AF: 0.0300 AC: 43863 AN: 1461846 Hom.: 716 Cov.: 32 AF XY: 0.0296 AC XY: 21509 AN XY: 727226

African (AFR) AF: 0.00490 AC: 164 AN: 33480

American (AMR) AF: 0.0185 AC: 827 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0455 AC: 1188 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.00508 AC: 438 AN: 86258

European-Finnish (FIN) AF: 0.0116 AC: 619 AN: 53408

Middle Eastern (MID) AF: 0.0165 AC: 95 AN: 5768

European-Non Finnish (NFE) AF: 0.0348 AC: 38739 AN: 1111976

Other (OTH) AF: 0.0296 AC: 1788 AN: 60396

GnomAD4 genome AF: 0.0231 AC: 3510 AN: 152230 Hom.: 59 Cov.: 32 AF XY: 0.0216 AC XY: 1608 AN XY: 74440

African (AFR) AF: 0.00739 AC: 307 AN: 41544

American (AMR) AF: 0.0264 AC: 404 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0505 AC: 175 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4822

European-Finnish (FIN) AF: 0.00896 AC: 95 AN: 10606

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0355 AC: 2417 AN: 67998

Other (OTH) AF: 0.0227 AC: 48 AN: 2110

Alfa AF: 0.0324 Hom.: 68

Bravo AF: 0.0244

TwinsUK AF: 0.0353 AC: 131

ALSPAC AF: 0.0366 AC: 141

ESP6500AA AF: 0.00658 AC: 29

ESP6500EA AF: 0.0349 AC: 300

ExAC AF: 0.0214 AC: 2598

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.0395

EpiControl AF: 0.0385

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Mitochondrial DNA depletion syndrome 13 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.16
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.069
Sift	Benign	0.15	T
Sift4G	Uncertain	0.036	D
Polyphen		0.090	B
Vest4		0.066
MutPred		0.33		Loss of helix (P = 0.0033)
MPC		0.069
ClinPred		0.011	T
GERP RS		4.4
Varity_R		0.13
gMVP		0.44
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs34316889; hg19: chr6-99374760;