16-87334102-C-T

Variant summary

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

The NM_024735.5(FBXO31):c.1181G>A(p.Arg394Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00559 in 1,610,220 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R394R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0041 (3 hom., cov: 34)
  • Exomes 𝑓: 0.0057 (68 hom.)
• Consequence: FBXO31 NM_024735.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -3.08

Genes affected

FBXO31 (HGNC:16510): (F-box protein 31) This gene is a member of the F-box family. Members are classified into three classes according to the substrate interaction domain, FBW for WD40 repeats, FBL for leucing-rich repeats, and FBXO for other domains. This protein, classified into the last category because of the lack of a recognizable substrate binding domain, has been proposed to be a component of the SCF ubiquitination complex. It is thought to bind and recruit substrate for ubiquitination and degradation. This protein may have a role in regulating the cell cycle as well as dendrite growth and neuronal migration. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034515262).
• BP6: Variant 16-87334102-C-T is Benign according to our data. Variant chr16-87334102-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 376898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-87334102-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00411 (626/152334) while in subpopulation SAS AF= 0.0255 (123/4832). AF 95% confidence interval is 0.0218. There are 3 homozygotes in gnomad4. There are 329 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBXO31	NM_024735.5	c.1181G>A	p.Arg394Gln	missense_variant	8/9	ENST00000311635.12
FBXO31	NM_001282683.2	c.665G>A	p.Arg222Gln	missense_variant	9/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBXO31	ENST00000311635.12	c.1181G>A	p.Arg394Gln	missense_variant	8/9	1	NM_024735.5	P1
FBXO31	ENST00000636077.2	c.1268G>A	p.Arg423Gln	missense_variant	9/10	5
FBXO31	ENST00000618298.6	c.665G>A	p.Arg222Gln	missense_variant	8/9	5
FBXO31	ENST00000565593.1	c.307G>A	p.Gly103Ser	missense_variant, NMD_transcript_variant	2/3	5

Frequencies

GnomAD3 genomes AF: 0.00413 AC: 628 AN: 152216 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0256

Gnomad FIN AF: 0.00640

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00501

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00650 AC: 1554 AN: 239092 Hom.: 17 AF XY: 0.00781 AC XY: 1023 AN XY: 131002

Gnomad AFR exome AF: 0.000618

Gnomad AMR exome AF: 0.000995

Gnomad ASJ exome AF: 0.00320

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0214

Gnomad FIN exome AF: 0.00771

Gnomad NFE exome AF: 0.00607

Gnomad OTH exome AF: 0.00442

GnomAD4 exome AF: 0.00574 AC: 8368 AN: 1457886 Hom.: 68 Cov.: 32 AF XY: 0.00633 AC XY: 4591 AN XY: 724950

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00135

Gnomad4 ASJ exome AF: 0.00269

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0213

Gnomad4 FIN exome AF: 0.00830

Gnomad4 NFE exome AF: 0.00504

Gnomad4 OTH exome AF: 0.00482

GnomAD4 genome AF: 0.00411 AC: 626 AN: 152334 Hom.: 3 Cov.: 34 AF XY: 0.00442 AC XY: 329 AN XY: 74502

Gnomad4 AFR AF: 0.000938

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0255

Gnomad4 FIN AF: 0.00640

Gnomad4 NFE AF: 0.00501

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00466 Hom.: 0

Bravo AF: 0.00319

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00115 AC: 5

ESP6500EA AF: 0.00410 AC: 35

ExAC AF: 0.00687 AC: 826

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.00480

EpiControl AF: 0.00510

ClinVar

Significance: Benign/Likely 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	Invitae	Dec 31, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 08, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	0.044
Dann	Benign	0.88
DEOGEN2	Benign	0.047	T;T
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.58	T;T
MetaRNN	Benign	0.0035	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N;.
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.23	N;.
REVEL	Benign	0.023
Sift	Benign	0.68	T;.
Sift4G	Benign	0.63	T;T
Polyphen		0.0010	B;.
Vest4		0.15
MVP		0.33
MPC		0.95
ClinPred		0.0031	T
GERP RS		-8.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.020
gMVP		0.17

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

Publications

LitVar

Other links and lift over

dbSNP: rs34412175; hg19: chr16-87367708; COSMIC: COSV61147582;