Genetic Variant BTRC:p.Gln78Lys (chr10-101462056-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_033637.4(BTRC):c.232C>A(p.Gln78Lys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

BTRC
NM_033637.4 missense, splice_region

Scores

Splicing: ADA: 0.9168

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.74

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033637.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BTRC	NM_033637.4	MANE Select	c.232C>A	p.Gln78Lys	missense splice_region	Exon 3 of 15	NP_378663.1	Q9Y297-1
BTRC	NM_003939.5		c.124C>A	p.Gln42Lys	missense splice_region	Exon 2 of 14	NP_003930.1	Q9Y297-2
BTRC	NM_001256856.2		c.157-17312C>A		intron	N/A	NP_001243785.1	B7Z3H4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BTRC	ENST00000370187.8	TSL:1 MANE Select	c.232C>A	p.Gln78Lys	missense splice_region	Exon 3 of 15	ENSP00000359206.3	Q9Y297-1
BTRC	ENST00000408038.6	TSL:1	c.124C>A	p.Gln42Lys	missense splice_region	Exon 2 of 14	ENSP00000385339.2	Q9Y297-2
BTRC	ENST00000393441.8	TSL:1	c.157-17312C>A		intron	N/A	ENSP00000377088.5	B7Z3H4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.062

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.012

MetaRNN

Uncertain

0.48

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.34

PhyloP100

5.7

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.19

REVEL

Benign

0.27

Sift

Uncertain

0.0070

Sift4G

Benign

0.14

Polyphen

0.32

Vest4

0.61

MutPred

0.51

Loss of ubiquitination at K73 (P = 0.02)

MVP

0.65

MPC

0.74

ClinPred

0.92

GERP RS

6.2

Varity_R

0.21

gMVP

0.80

Mutation Taster

=46/54

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.92

dbscSNV1_RF

Pathogenic

0.78

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over