Genetic Variant BRCC3:p.Val12_His13insGlnAlaValGlnAlaVal (chrX-155071541-T-TGGTGCAGGCGGTGCAGGC) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4BS2

The NM_001018055.3(BRCC3):c.18_35dupGCAGGCGGTGCAGGCGGT(p.Val12_His13insGlnAlaValGlnAlaVal) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,091,549 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.000021 ( 0 hom. 10 hem. )

Consequence

BRCC3
NM_001018055.3 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.55

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001018055.3.

BS2

High Hemizygotes in GnomAdExome4 at 10 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCC3	NM_001018055.3 link	c.18_35dupGCAGGCGGTGCAGGCGGT	p.Val12_His13insGlnAlaValGlnAlaVal	disruptive_inframe_insertion	Exon 1 of 11	ENST00000330045.12	NP_001018065.1	P46736-2
BRCC3	NM_024332.4 link	c.18_35dupGCAGGCGGTGCAGGCGGT	p.Val12_His13insGlnAlaValGlnAlaVal	disruptive_inframe_insertion	Exon 1 of 12		NP_077308.1	P46736-1
BRCC3	NM_001242640.2 link	c.18_35dupGCAGGCGGTGCAGGCGGT	p.Val12_His13insGlnAlaValGlnAlaVal	disruptive_inframe_insertion	Exon 1 of 11		NP_001229569.1	P46736-3
BRCC3	XM_005274751.5 link	c.18_35dupGCAGGCGGTGCAGGCGGT	p.Val12_His13insGlnAlaValGlnAlaVal	disruptive_inframe_insertion	Exon 1 of 12		XP_005274808.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCC3	ENST00000330045.12 link	c.18_35dupGCAGGCGGTGCAGGCGGT	p.Val12_His13insGlnAlaValGlnAlaVal	disruptive_inframe_insertion	Exon 1 of 11	1	NM_001018055.3	ENSP00000328641.7		P46736-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000184

AC:

AN:

163208

Hom.:

AF XY:

0.0000374

AC XY:

AN XY:

53502

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:

0.000118

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000141

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000211

AC:

AN:

1091549

Hom.:

Cov.:

AF XY:

0.0000279

AC XY:

AN XY:

358241

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:

0.000227

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000107

Gnomad4 OTH exome

AF:

0.0000436

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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.

X-155071541-TGGTGCAGGC-TGGTGCAGGCGGTGCAGGCGGTGCAGGC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over