10-101354217-C-T

Variant names:

• chr10-101354217-C-T
• rs1408160078
• NM_033637.4:c.37C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033637.4(BTRC):​c.37C>T​(p.Leu13Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L13I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: BTRC NM_033637.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.48
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21001294).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BTRC	NM_033637.4	MANE Select	c.37C>T	p.Leu13Phe	missense	Exon 1 of 15	NP_378663.1	Q9Y297-1
	BTRC	NM_001256856.2		c.37C>T	p.Leu13Phe	missense	Exon 1 of 14	NP_001243785.1	B7Z3H4
	BTRC	NM_003939.5		c.37C>T	p.Leu13Phe	missense	Exon 1 of 14	NP_003930.1	Q9Y297-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BTRC	ENST00000370187.8	TSL:1 MANE Select	c.37C>T	p.Leu13Phe	missense	Exon 1 of 15	ENSP00000359206.3	Q9Y297-1
	BTRC	ENST00000393441.8	TSL:1	c.37C>T	p.Leu13Phe	missense	Exon 1 of 14	ENSP00000377088.5	B7Z3H4
	BTRC	ENST00000408038.6	TSL:1	c.37C>T	p.Leu13Phe	missense	Exon 1 of 14	ENSP00000385339.2	Q9Y297-2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000657 AC: 1 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74358

African (AFR) AF: 0.0000241 AC: 1 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.010	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.067	T
Eigen	Benign	0.0029
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.55	N
PhyloP100		3.5
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.13
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.043	D
Polyphen		0.14	B
Vest4		0.39
MutPred		0.33		Gain of methylation at K11 (P = 0.095)
MVP		0.36
MPC		0.63
ClinPred		0.95	D
GERP RS		5.1
PromoterAI		0.020	Neutral
Varity_R		0.30
gMVP		0.57
Mutation Taster		=77/23	polymorphism

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

Other links and lift over

dbSNP: rs1408160078; hg19: chr10-103113974;