NM_012179.4:c.949C>T

Variant names:

• chr22-32491163-C-T
• rs9726
• NM_012179.4:c.949C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_012179.4(FBXO7):​c.949C>T​(p.Leu317Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.403 in 1,606,990 control chromosomes in the GnomAD database, including 136,332 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (13664 hom., cov: 31)
  • Exomes 𝑓: 0.40 (122668 hom.)
• Consequence: FBXO7 NM_012179.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.36
• Publications: 31 publications found

Genes affected

FBXO7 (HGNC:13586): (F-box protein 7) This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of the ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 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 belongs to the Fbxs class and it may play a role in regulation of hematopoiesis. Alternatively spliced transcript variants of this gene have been identified with the full-length natures of only some variants being determined. [provided by RefSeq, Jul 2008]

FBXO7 Gene-Disease associations (from GenCC):

• parkinsonian-pyramidal syndrome

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 22-32491163-C-T is Benign according to our data. Variant chr22-32491163-C-T is described in ClinVar as Benign. ClinVar VariationId is 341314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.36 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.67 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012179.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXO7	NM_012179.4	MANE Select	c.949C>T	p.Leu317Leu	synonymous	Exon 6 of 9	NP_036311.3
	FBXO7	NM_001033024.2		c.712C>T	p.Leu238Leu	synonymous	Exon 6 of 9	NP_001028196.1	Q9Y3I1-2
	FBXO7	NM_001257990.2		c.607C>T	p.Leu203Leu	synonymous	Exon 6 of 9	NP_001244919.1	Q9Y3I1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXO7	ENST00000266087.12	TSL:1 MANE Select	c.949C>T	p.Leu317Leu	synonymous	Exon 6 of 9	ENSP00000266087.7	Q9Y3I1-1
	FBXO7	ENST00000886524.1		c.949C>T	p.Leu317Leu	synonymous	Exon 6 of 10	ENSP00000556583.1
	FBXO7	ENST00000920428.1		c.949C>T	p.Leu317Leu	synonymous	Exon 6 of 9	ENSP00000590487.1

Frequencies

GnomAD3 genomes AF: 0.416 AC: 63190 AN: 151768 Hom.: 13645 Cov.: 31

Gnomad AFR AF: 0.386

Gnomad AMI AF: 0.347

Gnomad AMR AF: 0.505

Gnomad ASJ AF: 0.418

Gnomad EAS AF: 0.689

Gnomad SAS AF: 0.461

Gnomad FIN AF: 0.496

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.380

Gnomad OTH AF: 0.397

GnomAD2 exomes AF: 0.453 AC: 113653 AN: 251146 AF XY: 0.447

Gnomad AFR exome AF: 0.386

Gnomad AMR exome AF: 0.606

Gnomad ASJ exome AF: 0.408

Gnomad EAS exome AF: 0.687

Gnomad FIN exome AF: 0.481

Gnomad NFE exome AF: 0.371

Gnomad OTH exome AF: 0.430

GnomAD4 exome AF: 0.402 AC: 584951 AN: 1455106 Hom.: 122668 Cov.: 30 AF XY: 0.404 AC XY: 292696 AN XY: 724178

African (AFR) AF: 0.379 AC: 12626 AN: 33310

American (AMR) AF: 0.595 AC: 26604 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.406 AC: 10597 AN: 26088

East Asian (EAS) AF: 0.736 AC: 29171 AN: 39608

South Asian (SAS) AF: 0.467 AC: 40167 AN: 86082

European-Finnish (FIN) AF: 0.469 AC: 25002 AN: 53344

Middle Eastern (MID) AF: 0.421 AC: 2419 AN: 5752

European-Non Finnish (NFE) AF: 0.374 AC: 413358 AN: 1106080

Other (OTH) AF: 0.416 AC: 25007 AN: 60130

GnomAD4 genome AF: 0.416 AC: 63241 AN: 151884 Hom.: 13664 Cov.: 31 AF XY: 0.426 AC XY: 31578 AN XY: 74196

African (AFR) AF: 0.387 AC: 16023 AN: 41456

American (AMR) AF: 0.505 AC: 7716 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 1449 AN: 3466

East Asian (EAS) AF: 0.689 AC: 3555 AN: 5160

South Asian (SAS) AF: 0.460 AC: 2209 AN: 4800

European-Finnish (FIN) AF: 0.496 AC: 5214 AN: 10502

Middle Eastern (MID) AF: 0.442 AC: 130 AN: 294

European-Non Finnish (NFE) AF: 0.380 AC: 25788 AN: 67926

Other (OTH) AF: 0.400 AC: 841 AN: 2104

Alfa AF: 0.396 Hom.: 13616

Bravo AF: 0.418

Asia WGS AF: 0.594 AC: 2063 AN: 3478

EpiCase AF: 0.375

EpiControl AF: 0.375

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	Parkinsonian-pyramidal syndrome (5)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	11
DANN	Benign	0.75
PhyloP100		2.4
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs9726; hg19: chr22-32887150; COSMIC: COSV56676791; COSMIC: COSV56676791;