7-5500614-T-C

Position:

• chr7-5500614-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_024963.6(FBXL18):​c.1655A>G​(p.Asn552Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,613,266 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 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. N552K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0093 (35 hom., cov: 33)
  • Exomes 𝑓: 0.00095 (21 hom.)
• Consequence: FBXL18 NM_024963.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.22

Genes affected

FBXL18 (HGNC:21874): (F-box and leucine rich repeat protein 18) The protein encoded by this gene is a member of a family of proteins that contain an approximately 40-amino acid F-box motif. This motif is important for interaction with SKP1 and for targeting some proteins for degradation. The encoded protein has been shown to control the cellular level of FBXL7, a protein that induces mitotic arrest, by targeting it for polyubiquitylation and proteasomal degradation. Members of the F-box protein family, such as FBXL18, are characterized by an approximately 40-amino acid F-box motif. F-box proteins interact with SKP1 through the F box, and they interact with ubiquitination targets through other protein interaction domains. [provided by RefSeq, Mar 2016]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024707317).
• BP6: Variant 7-5500614-T-C is Benign according to our data. Variant chr7-5500614-T-C is described in ClinVar as [Benign]. Clinvar id is 786894.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00935 (1423/152268) while in subpopulation AFR AF= 0.0329 (1367/41560). AF 95% confidence interval is 0.0314. There are 35 homozygotes in gnomad4. There are 706 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 35 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FBXL18	NM_024963.6	c.1655A>G	p.Asn552Ser	missense_variant	3/5	ENST00000382368.8	NP_079239.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FBXL18	ENST00000382368.8	c.1655A>G	p.Asn552Ser	missense_variant	3/5	5	NM_024963.6	ENSP00000371805.3
FBXL18	ENST00000458142.1	c.1304A>G	p.Asn435Ser	missense_variant	1/3	2		ENSP00000405896.1
FBXL18	ENST00000415009.5	n.1655A>G		non_coding_transcript_exon_variant	3/7	2		ENSP00000415064.1

Frequencies

GnomAD3 genomes AF: 0.00927 AC: 1410 AN: 152150 Hom.: 34 Cov.: 33

Gnomad AFR AF: 0.0327

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00222 AC: 550 AN: 247828 Hom.: 5 AF XY: 0.00172 AC XY: 232 AN XY: 134960

Gnomad AFR exome AF: 0.0328

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000558

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000446

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000950 AC: 1388 AN: 1460998 Hom.: 21 Cov.: 30 AF XY: 0.000835 AC XY: 607 AN XY: 726840

Gnomad4 AFR exome AF: 0.0347

Gnomad4 AMR exome AF: 0.00145

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.00181

GnomAD4 genome AF: 0.00935 AC: 1423 AN: 152268 Hom.: 35 Cov.: 33 AF XY: 0.00948 AC XY: 706 AN XY: 74434

Gnomad4 AFR AF: 0.0329

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.00292 Hom.: 3

Bravo AF: 0.0103

ESP6500AA AF: 0.0320 AC: 133

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00287 AC: 347

Asia WGS AF: 0.00346 AC: 13 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 08, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	16
DANN	Benign	0.70
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.11	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.9	N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.044
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.041
MVP		0.54
MPC		0.42
ClinPred		0.00072	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs74478333; hg19: chr7-5540245;