X-155116113-T-C

Position:

chrX-155116113-T-C

Variant summary

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

The NM_001018055.3(BRCC3):c.605T>C(p.Val202Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000912 in 1,206,226 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 31 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. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000096 ( 0 hom. 31 hem. )

Consequence

BRCC3
NM_001018055.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.54

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=0.18838665).

BS2

High Hemizygotes in GnomAdExome4 at 31 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
BRCC3	NM_001018055.3 linkuse as main transcript	c.605T>C	p.Val202Ala	missense_variant	8/11	ENST00000330045.12	NP_001018065.1
BRCC3	NM_024332.4 linkuse as main transcript	c.680T>C	p.Val227Ala	missense_variant	9/12		NP_077308.1
BRCC3	NM_001242640.2 linkuse as main transcript	c.608T>C	p.Val203Ala	missense_variant	8/11		NP_001229569.1
BRCC3	XM_005274751.5 linkuse as main transcript	c.683T>C	p.Val228Ala	missense_variant	9/12		XP_005274808.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCC3	ENST00000330045.12 linkuse as main transcript	c.605T>C	p.Val202Ala	missense_variant	8/11	1	NM_001018055.3	ENSP00000328641	P3	P46736-2

Frequencies

GnomAD3 genomes

AF:

0.0000449

AC:

AN:

111477

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33659

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000943

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000113

AC:

AN:

177195

Hom.:

AF XY:

0.0000157

AC XY:

AN XY:

63631

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000253

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000959

AC:

105

AN:

1094749

Hom.:

Cov.:

AF XY:

0.0000860

AC XY:

AN XY:

360661

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.000121

Gnomad4 OTH exome

AF:

0.0000653

GnomAD4 genome

AF:

0.0000449

AC:

AN:

111477

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33659

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000943

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 23, 2024

The c.680T>C (p.V227A) alteration is located in exon 9 (coding exon 9) of the BRCC3 gene. This alteration results from a T to C substitution at nucleotide position 680, causing the valine (V) at amino acid position 227 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2023

BRCC3: PM2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.048

.;.;T;T;.;.;.

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.65

T;T;T;T;T;T;T

M_CAP

Benign

0.0072

MetaRNN

Benign

0.19

T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.66

.;.;N;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.62

PROVEAN

Benign

0.030

N;N;N;N;N;.;.

REVEL

Benign

0.031

Sift

Benign

0.55

T;T;T;T;T;.;.

Sift4G

Benign

0.63

T;T;T;T;T;T;T

Polyphen

0.0040, 0.069

.;B;B;.;.;.;.

Vest4

0.28

MutPred

0.39

.;.;Loss of sheet (P = 0.0315);.;Loss of sheet (P = 0.0315);.;Loss of sheet (P = 0.0315);

MVP

0.82

MPC

1.5

ClinPred

0.18

GERP RS

3.6

Varity_R

0.15

gMVP

0.94

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

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