chrX-155072340-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001018055.3(BRCC3):c.137C>T(p.Thr46Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000093 in 1,075,446 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 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. T46K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.3e-7 ( 0 hom. 0 hem. )

Consequence

BRCC3
NM_001018055.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0220

Publications

0 publications found

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 was made for transcript

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=0.16738701).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001018055.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BRCC3	NM_001018055.3	MANE Select	c.137C>T	p.Thr46Ile	missense	Exon 2 of 11	NP_001018065.1	P46736-2
BRCC3	NM_024332.4		c.137C>T	p.Thr46Ile	missense	Exon 2 of 12	NP_077308.1	P46736-1
BRCC3	NM_001242640.2		c.137C>T	p.Thr46Ile	missense	Exon 2 of 11	NP_001229569.1	P46736-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BRCC3	ENST00000330045.12	TSL:1 MANE Select	c.137C>T	p.Thr46Ile	missense	Exon 2 of 11	ENSP00000328641.7	P46736-2
BRCC3	ENST00000369462.5	TSL:1	c.137C>T	p.Thr46Ile	missense	Exon 2 of 12	ENSP00000358474.1	P46736-1
BRCC3	ENST00000340647.8	TSL:2	c.137C>T	p.Thr46Ile	missense	Exon 2 of 11	ENSP00000344103.4	P46736-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.30e-7

AC:

AN:

1075446

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

342756

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25939

American (AMR)

AF:

0.00

AC:

AN:

34616

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19156

East Asian (EAS)

AF:

0.00

AC:

AN:

29973

South Asian (SAS)

AF:

0.00

AC:

AN:

52832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40438

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4049

European-Non Finnish (NFE)

AF:

0.00000121

AC:

AN:

823132

Other (OTH)

AF:

0.00

AC:

AN:

45311

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.81

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.13

FATHMM_MKL

Benign

0.071

LIST_S2

Benign

0.23

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.3

PhyloP100

0.022

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.11

REVEL

Benign

0.059

Sift

Benign

0.63

Sift4G

Benign

0.45

Polyphen

0.0

Vest4

0.13

MutPred

0.49

Loss of phosphorylation at T46 (P = 0.0096)

MVP

0.82

MPC

1.3

ClinPred

0.062

GERP RS

2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.070

gMVP

0.42

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over