chrX-155072340-C-A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001018055.3(BRCC3):c.137C>A(p.Thr46Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000043 in 1,187,414 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000045 ( 0 hom. 13 hem. )

Consequence

BRCC3
NM_001018055.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0220

Variant links:

Genes affected

BRCC3 (HGNC:24185): (BRCA1/BRCA2-containing complex subunit 3) This gene encodes a subunit of the BRCA1-BRCA2-containing complex (BRCC), which is an E3 ubiquitin ligase. This complex plays a role in the DNA damage response, where it is responsible for the stable accumulation of BRCA1 at DNA break sites. The component encoded by this gene can specifically cleave Lys 63-linked polyubiquitin chains, and it regulates the abundance of these polyubiquitin chains in chromatin. The loss of this gene results in abnormal angiogenesis and is associated with syndromic moyamoya, a cerebrovascular angiopathy. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 5. [provided by RefSeq, Jun 2011]

BRCC3 links:

MTCP1 (HGNC:7423): (mature T cell proliferation 1) This gene was identified by involvement in some t(X;14) translocations associated with mature T-cell proliferations. This region has a complex gene structure, with a common promoter and 5' exon spliced to two different sets of 3' exons that encode two different proteins. This gene represents the upstream 13 kDa protein that is a member of the TCL1 family. This protein may be involved in leukemogenesis. [provided by RefSeq, Mar 2009]

MTCP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21430647).

BS2

High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCC3	NM_001018055.3 link	c.137C>A	p.Thr46Lys	missense_variant	Exon 2 of 11	ENST00000330045.12	NP_001018065.1	P46736-2
BRCC3	NM_024332.4 link	c.137C>A	p.Thr46Lys	missense_variant	Exon 2 of 12		NP_077308.1	P46736-1
BRCC3	NM_001242640.2 link	c.137C>A	p.Thr46Lys	missense_variant	Exon 2 of 11		NP_001229569.1	P46736-3
BRCC3	XM_005274751.5 link	c.137C>A	p.Thr46Lys	missense_variant	Exon 2 of 12		XP_005274808.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCC3	ENST00000330045.12 link	c.137C>A	p.Thr46Lys	missense_variant	Exon 2 of 11	1	NM_001018055.3	ENSP00000328641.7		P46736-2

Frequencies

GnomAD3 genomes

AF:

0.0000268

AC:

AN:

111972

Hom.:

Cov.:

AF XY:

0.0000586

AC XY:

AN XY:

34150

show subpopulations

Gnomad AFR

AF:

0.0000325

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:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000170

AC:

AN:

176117

Hom.:

AF XY:

0.00

AC XY:

AN XY:

62315

show subpopulations

Gnomad AFR exome

AF:

0.0000823

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000251

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000446

AC:

AN:

1075442

Hom.:

Cov.:

AF XY:

0.0000379

AC XY:

AN XY:

342754

show subpopulations

Gnomad4 AFR exome

AF:

0.0000386

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000559

Gnomad4 OTH exome

AF:

0.0000221

GnomAD4 genome

AF:

0.0000268

AC:

AN:

111972

Hom.:

Cov.:

AF XY:

0.0000586

AC XY:

AN XY:

34150

show subpopulations

Gnomad4 AFR

AF:

0.0000325

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000376

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 13, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.137C>A (p.T46K) alteration is located in exon 2 (coding exon 2) of the BRCC3 gene. This alteration results from a C to A substitution at nucleotide position 137, causing the threonine (T) at amino acid position 46 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.69

CADD

Benign

9.9

DANN

Benign

0.78

DEOGEN2

Benign

0.079

.;.;.;T;.;.

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.20

T;T;T;T;T;T

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.18

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.96

L;L;L;L;.;.

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.29

N;N;N;N;.;.

REVEL

Benign

0.028

Sift

Benign

0.082

T;T;T;T;.;.

Sift4G

Benign

0.97

T;T;T;T;T;T

Polyphen

0.068

B;B;.;B;.;.

Vest4

0.30

MutPred

0.52

Gain of ubiquitination at T46 (P = 0.0085);Gain of ubiquitination at T46 (P = 0.0085);Gain of ubiquitination at T46 (P = 0.0085);Gain of ubiquitination at T46 (P = 0.0085);Gain of ubiquitination at T46 (P = 0.0085);Gain of ubiquitination at T46 (P = 0.0085);

MVP

0.82

MPC

1.6

ClinPred

0.0078

GERP RS

2.0

Varity_R

0.11

gMVP

0.50

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over