rs4151060

chr10-101538342-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.030 (121 hom., cov: 32)
  • Exomes 𝑓: 0.046 (1902 hom.)
• Consequence: BTRC NM_033637.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 9.57

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
BTRC	NM_033637.4	c.1627G>T	p.Ala543Ser	missense_variant	13/15	ENST00000370187.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BTRC	ENST00000370187.8	c.1627G>T	p.Ala543Ser	missense_variant	13/15	1	NM_033637.4	A1
BTRC	ENST00000393441.8	c.1549G>T	p.Ala517Ser	missense_variant	12/14	1
BTRC	ENST00000408038.6	c.1519G>T	p.Ala507Ser	missense_variant	12/14	1		P4
BTRC	ENST00000493877.1	n.250G>T		non_coding_transcript_exon_variant	3/4	5

Frequencies

GnomAD3 genomes AF: 0.0303 AC: 4611 AN: 152162 Hom.: 121 Cov.: 32

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

GnomAD3 exomes AF: 0.0294 AC: 7389 AN: 251454 Hom.: 159 AF XY: 0.0297 AC XY: 4039 AN XY: 135902

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 SAS exome AF: 0.00843

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.: 31 AF XY: 0.0450 AC XY: 32708 AN XY: 727050

Gnomad4 AFR exome AF: 0.00735

Gnomad4 AMR exome AF: 0.0214

Gnomad4 ASJ exome AF: 0.00318

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00861

Gnomad4 FIN exome AF: 0.0294

Gnomad4 NFE exome AF: 0.0555

Gnomad4 OTH exome AF: 0.0396

GnomAD4 genome AF: 0.0303 AC: 4610 AN: 152280 Hom.: 121 Cov.: 32 AF XY: 0.0288 AC XY: 2146 AN XY: 74466

Gnomad4 AFR AF: 0.00883

Gnomad4 AMR AF: 0.0252

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00436

Gnomad4 FIN AF: 0.0315

Gnomad4 NFE AF: 0.0496

Gnomad4 OTH AF: 0.0274

Alfa AF: 0.0424 Hom.: 258

Bravo AF: 0.0295

TwinsUK AF: 0.0542 AC: 201

ALSPAC AF: 0.0550 AC: 212

ESP6500AA AF: 0.0113 AC: 50

ESP6500EA AF: 0.0478 AC: 411

ExAC AF: 0.0286 AC: 3472

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.0434

EpiControl AF: 0.0465

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

BTRC-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 07, 2019

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	22
Dann	Benign	0.97
Eigen	Benign	-0.013
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
MetaRNN	Benign	0.0027	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.70	T
REVEL	Benign	0.14
Sift4G	Benign	0.75	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.45
MPC		0.53
ClinPred		0.063	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.18

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: rs4151060; hg19: chr10-103298099;