12-116949614-G-A

Position:

• chr12-116949614-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_153348.3(FBXW8):​c.589-4G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,614,072 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (12 hom., cov: 33)
  • Exomes 𝑓: 0.00065 (14 hom.)
• Consequence: FBXW8 NM_153348.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001972
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.101

Genes affected

FBXW8 (HGNC:13597): (F-box and WD repeat domain containing 8) This gene encodes a member of the F-box protein family, members of which are characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into three classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene contains a WD-40 domain, in addition to an F-box motif, so it belongs to the Fbw class. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 12-116949614-G-A is Benign according to our data. Variant chr12-116949614-G-A is described in ClinVar as [Benign]. Clinvar id is 773686.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.006 (914/152308) while in subpopulation AFR AF= 0.0207 (860/41574). AF 95% confidence interval is 0.0195. There are 12 homozygotes in gnomad4. There are 420 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXW8	NM_153348.3	c.589-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000652555.1	NP_699179.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXW8	ENST00000652555.1	c.589-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_153348.3	ENSP00000498999	P1
FBXW8	ENST00000309909.10	c.277-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000310686
FBXW8	ENST00000455858.2	c.391-4G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000389144
	ENST00000617795.1	n.1809C>T		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.00598 AC: 910 AN: 152190 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.0206

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00528

GnomAD3 exomes AF: 0.00163 AC: 409 AN: 251452 Hom.: 3 AF XY: 0.00110 AC XY: 150 AN XY: 135902

Gnomad AFR exome AF: 0.0216

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000647 AC: 946 AN: 1461764 Hom.: 14 Cov.: 30 AF XY: 0.000517 AC XY: 376 AN XY: 727192

Gnomad4 AFR exome AF: 0.0216

Gnomad4 AMR exome AF: 0.00134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000675

Gnomad4 OTH exome AF: 0.00123

GnomAD4 genome AF: 0.00600 AC: 914 AN: 152308 Hom.: 12 Cov.: 33 AF XY: 0.00564 AC XY: 420 AN XY: 74476

Gnomad4 AFR AF: 0.0207

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00522

Alfa AF: 0.00296 Hom.: 3

Bravo AF: 0.00682

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 18, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.99
DANN	Benign	0.80

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00020
dbscSNV1_RF	Benign	0.0040
SpliceAI score (max)		0.020		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: rs74977947; hg19: chr12-117387419;