10-101521877-C-G

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.556+7C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.215 in 1,580,108 control chromosomes in the GnomAD database, including 45,652 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (8864 hom., cov: 32)
  • Exomes 𝑓: 0.21 (36788 hom.)
• Consequence: BTRC NM_033637.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002390
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.752

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 (BayesDel_noAF=-0.84).
• BP6: Variant 10-101521877-C-G is Benign according to our data. Variant chr10-101521877-C-G is described in ClinVar as [Benign]. Clinvar id is 1222592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.58 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BTRC	NM_033637.4	c.556+7C>G		splice_region_variant, intron_variant		ENST00000370187.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BTRC	ENST00000370187.8	c.556+7C>G		splice_region_variant, intron_variant		1	NM_033637.4	A1

Frequencies

GnomAD3 genomes AF: 0.297 AC: 45097 AN: 151596 Hom.: 8853 Cov.: 32

Gnomad AFR AF: 0.535

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.213

Gnomad EAS AF: 0.598

Gnomad SAS AF: 0.262

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.162

Gnomad NFE AF: 0.177

Gnomad OTH AF: 0.295

GnomAD3 exomes AF: 0.256 AC: 64051 AN: 249734 Hom.: 10553 AF XY: 0.249 AC XY: 33647 AN XY: 135058

Gnomad AFR exome AF: 0.542

Gnomad AMR exome AF: 0.257

Gnomad ASJ exome AF: 0.226

Gnomad EAS exome AF: 0.622

Gnomad SAS exome AF: 0.260

Gnomad FIN exome AF: 0.163

Gnomad NFE exome AF: 0.177

Gnomad OTH exome AF: 0.226

GnomAD4 exome AF: 0.206 AC: 294725 AN: 1428392 Hom.: 36788 Cov.: 29 AF XY: 0.206 AC XY: 146913 AN XY: 712288

Gnomad4 AFR exome AF: 0.549

Gnomad4 AMR exome AF: 0.254

Gnomad4 ASJ exome AF: 0.224

Gnomad4 EAS exome AF: 0.576

Gnomad4 SAS exome AF: 0.253

Gnomad4 FIN exome AF: 0.164

Gnomad4 NFE exome AF: 0.176

Gnomad4 OTH exome AF: 0.244

GnomAD4 genome AF: 0.298 AC: 45148 AN: 151716 Hom.: 8864 Cov.: 32 AF XY: 0.295 AC XY: 21851 AN XY: 74128

Gnomad4 AFR AF: 0.534

Gnomad4 AMR AF: 0.236

Gnomad4 ASJ AF: 0.213

Gnomad4 EAS AF: 0.597

Gnomad4 SAS AF: 0.263

Gnomad4 FIN AF: 0.159

Gnomad4 NFE AF: 0.177

Gnomad4 OTH AF: 0.293

Alfa AF: 0.213 Hom.: 1350

Bravo AF: 0.317

Asia WGS AF: 0.406 AC: 1411 AN: 3476

EpiCase AF: 0.176

EpiControl AF: 0.183

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2021	- -

BTRC-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 26, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	10
Dann	Benign	0.54

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000024
dbscSNV1_RF	Benign	0.0020
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: rs6584429; hg19: chr10-103281634; COSMIC: COSV64563239; COSMIC: COSV64563239;