16-87334102-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 14/20 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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -3.08

Publications

5 publications found

Variant links:

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]

FBXO31 Gene-Disease associations (from GenCC):

autosomal recessive non-syndromic intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
cerebral palsy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
intellectual disability, autosomal recessive
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
intellectual disability, autosomal recessive 45
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

FBXO31 links:

ENSG00000131152 (HGNC:):

ENSG00000131152 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 376898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FBXO31	NM_024735.5 link	c.1181G>A	p.Arg394Gln	missense_variant	Exon 8 of 9	ENST00000311635.12	NP_079011.3
FBXO31	NM_001282683.2 link	c.665G>A	p.Arg222Gln	missense_variant	Exon 9 of 10		NP_001269612.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FBXO31	ENST00000311635.12 link	c.1181G>A	p.Arg394Gln	missense_variant	Exon 8 of 9	1	NM_024735.5	ENSP00000310841.4
ENSG00000131152	ENST00000568879.1 link	c.170G>A	p.Arg57Gln	missense_variant	Exon 1 of 5	4		ENSP00000454386.1

Frequencies

GnomAD3 genomes

AF:

0.00413

AC:

628

AN:

152216

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00650

AC:

1554

AN:

239092

AF XY:

0.00781

show subpopulations

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 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.:

Cov.:

AF XY:

0.00633

AC XY:

4591

AN XY:

724950

show subpopulations

African (AFR)

AF:

0.00102

AC:

AN:

33386

American (AMR)

AF:

0.00135

AC:

AN:

44530

Ashkenazi Jewish (ASJ)

AF:

0.00269

AC:

AN:

25978

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39614

South Asian (SAS)

AF:

0.0213

AC:

1835

AN:

86052

European-Finnish (FIN)

AF:

0.00830

AC:

432

AN:

52018

Middle Eastern (MID)

AF:

0.00819

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.00504

AC:

5599

AN:

1110388

Other (OTH)

AF:

0.00482

AC:

290

AN:

60184

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

534

1067

1601

2134

2668

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

214

428

642

856

1070

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00411

AC:

626

AN:

152334

Hom.:

Cov.:

AF XY:

0.00442

AC XY:

329

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.000938

AC:

AN:

41588

American (AMR)

AF:

0.00196

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.0255

AC:

123

AN:

4832

European-Finnish (FIN)

AF:

0.00640

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00501

AC:

341

AN:

68014

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

107

142

178

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00466

Hom.:

Bravo

AF:

0.00319

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.00115

AC:

ESP6500EA

AF:

0.00410

AC:

ExAC

AF:

0.00687

AC:

826

Asia WGS

AF:

0.00577

AC:

AN:

3478

EpiCase

AF:

0.00480

EpiControl

AF:

0.00510

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 08, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.044

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.047

T;T

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.3

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.58

T;T

MetaRNN

Benign

0.0035

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.14

N;.

PhyloP100

-3.1

PrimateAI

Uncertain

0.55

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

GERP RS

-8.8

PromoterAI

-0.011

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.020

gMVP

0.17

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over