rs6842544

Variant names:

• chr4-152411407-T-C
• rs6842544
• NM_001349798.2:c.397A>G

Your query was ambiguous. Multiple possible variants found:

• chr4-152411407-T-C
• chr4-152411407-T-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The NM_001349798.2(FBXW7):​c.397A>G​(p.Arg133Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000934 in 1,613,712 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0054 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (5 hom.)
• Consequence: FBXW7 NM_001349798.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 2.24
• Publications: 12 publications found

Genes affected

FBXW7 (HGNC:16712): (F-box and WD repeat domain containing 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 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 was previously referred to as FBX30, and belongs to the Fbws class; in addition to an F-box, this protein contains 7 tandem WD40 repeats. This protein binds directly to cyclin E and probably targets cyclin E for ubiquitin-mediated degradation. Mutations in this gene are detected in ovarian and breast cancer cell lines, implicating the gene's potential role in the pathogenesis of human cancers. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2012]

FBXW7 Gene-Disease associations (from GenCC):

• developmental delay, hypotonia, and impaired language

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• PP2: Missense variant in the FBXW7 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 24 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 3.7111 (above the threshold of 3.09). Trascript score misZ: 4.5266 (above the threshold of 3.09). GenCC associations: The gene is linked to developmental delay, hypotonia, and impaired language.
• BP4: Computational evidence support a benign effect (MetaRNN=0.004651934).
• BP6: Variant 4-152411407-T-C is Benign according to our data. Variant chr4-152411407-T-C is described in ClinVar as Benign. ClinVar VariationId is 134382.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00544 (828/152218) while in subpopulation AFR AF = 0.0187 (777/41556). AF 95% confidence interval is 0.0176. There are 7 homozygotes in GnomAd4. There are 392 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 828 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001349798.2. 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
	FBXW7	NM_001349798.2	MANE Select	c.397A>G	p.Arg133Gly	missense	Exon 4 of 14	NP_001336727.1
	FBXW7	NM_033632.3		c.397A>G	p.Arg133Gly	missense	Exon 2 of 12	NP_361014.1
	FBXW7	NM_001257069.1		c.397A>G	p.Arg133Gly	missense	Exon 4 of 4	NP_001243998.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FBXW7	ENST00000281708.10	TSL:1 MANE Select	c.397A>G	p.Arg133Gly	missense	Exon 4 of 14	ENSP00000281708.3
	FBXW7	ENST00000603548.6	TSL:1	c.397A>G	p.Arg133Gly	missense	Exon 2 of 12	ENSP00000474725.1
	FBXW7	ENST00000603841.1	TSL:1	c.397A>G	p.Arg133Gly	missense	Exon 1 of 11	ENSP00000474971.1

Frequencies

GnomAD3 genomes AF: 0.00544 AC: 828 AN: 152100 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00256

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00480

GnomAD2 exomes AF: 0.00144 AC: 360 AN: 250428 AF XY: 0.00105

Gnomad AFR exome AF: 0.0197

Gnomad AMR exome AF: 0.000872

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.000820

GnomAD4 exome AF: 0.000465 AC: 680 AN: 1461494 Hom.: 5 Cov.: 31 AF XY: 0.000432 AC XY: 314 AN XY: 727036

African (AFR) AF: 0.0161 AC: 540 AN: 33466

American (AMR) AF: 0.00110 AC: 49 AN: 44630

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5760

European-Non Finnish (NFE) AF: 0.0000144 AC: 16 AN: 1111892

Other (OTH) AF: 0.00121 AC: 73 AN: 60376

GnomAD4 genome AF: 0.00544 AC: 828 AN: 152218 Hom.: 7 Cov.: 32 AF XY: 0.00527 AC XY: 392 AN XY: 74420

African (AFR) AF: 0.0187 AC: 777 AN: 41556

American (AMR) AF: 0.00255 AC: 39 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68006

Other (OTH) AF: 0.00475 AC: 10 AN: 2106

Alfa AF: 0.00228 Hom.: 10

Bravo AF: 0.00651

ESP6500AA AF: 0.0182 AC: 80

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00180 AC: 219

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.90	L
PhyloP100		2.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.21
Sift	Uncertain	0.024	D
Sift4G	Benign	0.29	T
Polyphen		0.97	D
Vest4		0.73
MVP		0.51
MPC		0.53
ClinPred		0.029	T
GERP RS		4.3
PromoterAI		0.020	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.10
gMVP		0.11
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs6842544; hg19: chr4-153332559;