rs4151060

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_033637.4(BTRC):c.1627G>T(p.Ala543Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0448 in 1,613,758 control chromosomes in the GnomAD database, including 2,023 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 121 hom., cov: 32)

Exomes 𝑓: 0.046 ( 1902 hom. )

Consequence

BTRC
NM_033637.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 9.57

Publications

26 publications found

Variant links:

Genes affected

BTRC (HGNC:1144): (beta-transducin repeat containing E3 ubiquitin protein ligase) 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 belongs to the Fbws class; in addition to an F-box, this protein contains multiple WD-40 repeats. The encoded protein mediates degradation of CD4 via its interaction with HIV-1 Vpu. It has also been shown to ubiquitinate phosphorylated NFKBIA (nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha), targeting it for degradation and thus activating nuclear factor kappa-B. Alternatively spliced transcript variants have been described. A related pseudogene exists in chromosome 6. [provided by RefSeq, Mar 2012]

BTRC 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=0.0027300715).

BP6

Variant 10-101538342-G-T is Benign according to our data. Variant chr10-101538342-G-T is described in ClinVar as Benign. ClinVar VariationId is 1534223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0551 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTRC	NM_033637.4 link	c.1627G>T	p.Ala543Ser	missense_variant	Exon 13 of 15	ENST00000370187.8	NP_378663.1	Q9Y297-1A0A0S2Z4P6B2R8L3Q68DS0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BTRC	ENST00000370187.8 link	c.1627G>T	p.Ala543Ser	missense_variant	Exon 13 of 15	1	NM_033637.4	ENSP00000359206.3	Q9Y297-1
BTRC	ENST00000393441.8 link	c.1549G>T	p.Ala517Ser	missense_variant	Exon 12 of 14	1		ENSP00000377088.5	B7Z3H4
BTRC	ENST00000408038.6 link	c.1519G>T	p.Ala507Ser	missense_variant	Exon 12 of 14	1		ENSP00000385339.2	Q9Y297-2
BTRC	ENST00000493877.1 link	n.250G>T		non_coding_transcript_exon_variant	Exon 3 of 4	5

Frequencies

GnomAD3 genomes

AF:

0.0303

AC:

4611

AN:

152162

Hom.:

121

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00886

Gnomad AMI

AF:

0.0593

Gnomad AMR

AF:

0.0253

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00435

Gnomad FIN

AF:

0.0315

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0496

Gnomad OTH

AF:

0.0277

GnomAD2 exomes

AF:

0.0294

AC:

7389

AN:

251454

AF XY:

0.0297

show subpopulations

Gnomad AFR exome

AF:

0.00917

Gnomad AMR exome

AF:

0.0204

Gnomad ASJ exome

AF:

0.00278

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0303

Gnomad NFE exome

AF:

0.0474

Gnomad OTH exome

AF:

0.0339

GnomAD4 exome

AF:

0.0464

AC:

67745

AN:

1461478

Hom.:

1902

Cov.:

AF XY:

0.0450

AC XY:

32708

AN XY:

727050

show subpopulations

African (AFR)

AF:

0.00735

AC:

246

AN:

33476

American (AMR)

AF:

0.0214

AC:

956

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00318

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39696

South Asian (SAS)

AF:

0.00861

AC:

743

AN:

86254

European-Finnish (FIN)

AF:

0.0294

AC:

1572

AN:

53396

Middle Eastern (MID)

AF:

0.0142

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0555

AC:

61669

AN:

1111654

Other (OTH)

AF:

0.0396

AC:

2392

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

3005

6010

9015

12020

15025

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2346

4692

7038

9384

11730

<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:

0.0303

AC:

4610

AN:

152280

Hom.:

121

Cov.:

AF XY:

0.0288

AC XY:

2146

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00883

AC:

367

AN:

41554

American (AMR)

AF:

0.0252

AC:

385

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00375

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00436

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0315

AC:

334

AN:

10604

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0496

AC:

3375

AN:

68022

Other (OTH)

AF:

0.0274

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

222

444

667

889

1111

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<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:

0.0414

Hom.:

339

Bravo

AF:

0.0295

TwinsUK

AF:

0.0542

AC:

201

ALSPAC

AF:

0.0550

AC:

212

ESP6500AA

AF:

0.0113

AC:

ESP6500EA

AF:

0.0478

AC:

411

ExAC

AF:

0.0286

AC:

3472

Asia WGS

AF:

0.00491

AC:

AN:

3478

EpiCase

AF:

0.0434

EpiControl

AF:

0.0465

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

BTRC-related disorder

Benign:1

Mar 07, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.047

.;T;.

Eigen

Benign

-0.013

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D

MetaRNN

Benign

0.0027

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.17

.;N;.

PhyloP100

9.6

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.25

.;N;N

REVEL

Benign

0.14

Sift

Benign

0.47

.;T;T

Sift4G

Benign

0.75

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.45

MPC

0.53

ClinPred

0.063

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.18

gMVP

0.18

Mutation Taster

=84/16

polymorphism (auto)

(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