rs4151060

Variant names:

• chr10-101538342-G-T
• rs4151060
• NM_033637.4:c.1627G>T

Variant summary

Our verdict is Benign. The variant received -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. 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 9.57
• Publications: 26 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: 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.

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.1627G>T	p.Ala543Ser	missense	Exon 13 of 15	NP_378663.1	Q9Y297-1
	BTRC	NM_001256856.2		c.1549G>T	p.Ala517Ser	missense	Exon 12 of 14	NP_001243785.1	B7Z3H4
	BTRC	NM_003939.5		c.1519G>T	p.Ala507Ser	missense	Exon 12 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.1627G>T	p.Ala543Ser	missense	Exon 13 of 15	ENSP00000359206.3	Q9Y297-1
	BTRC	ENST00000393441.8	TSL:1	c.1549G>T	p.Ala517Ser	missense	Exon 12 of 14	ENSP00000377088.5	B7Z3H4
	BTRC	ENST00000408038.6	TSL:1	c.1519G>T	p.Ala507Ser	missense	Exon 12 of 14	ENSP00000385339.2	Q9Y297-2

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

GnomAD2 exomes AF: 0.0294 AC: 7389 AN: 251454 AF XY: 0.0297

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

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: 83 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 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: 82 AN: 5766

European-Non Finnish (NFE) AF: 0.0555 AC: 61669 AN: 1111654

Other (OTH) AF: 0.0396 AC: 2392 AN: 60380

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

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: 13 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00436 AC: 21 AN: 4822

European-Finnish (FIN) AF: 0.0315 AC: 334 AN: 10604

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0496 AC: 3375 AN: 68022

Other (OTH) AF: 0.0274 AC: 58 AN: 2116

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: 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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	BTRC-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.047	T
Eigen	Benign	-0.013
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.17	N
PhyloP100		9.6
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.14
Sift	Benign	0.47	T
Sift4G	Benign	0.75	T
Polyphen		0.0	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
Mutation Taster		=84/16	polymorphism (auto)

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: rs4151060; hg19: chr10-103298099;