Genetic Variant BRCC3:p.Val12_His13insGlnAlaVal (chrX-155071541-T-TGGTGCAGGC) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM4BS2

The NM_001018055.3(BRCC3):c.27_35dupGCAGGCGGT(p.Val12_His13insGlnAlaVal) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000183 in 1,203,965 control chromosomes in the GnomAD database, including 1 homozygotes. There are 87 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., 4 hem., cov: 23)

Exomes 𝑓: 0.00019 ( 1 hom. 83 hem. )

Consequence

BRCC3
NM_001018055.3 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.55

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001018055.3.

BS2

High AC in GnomAd4 at 11 AD,XL gene.

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.27_35dupGCAGGCGGT	p.Val12_His13insGlnAlaVal	disruptive_inframe_insertion	Exon 1 of 11	NP_001018065.1	P46736-2
BRCC3	NM_024332.4		c.27_35dupGCAGGCGGT	p.Val12_His13insGlnAlaVal	disruptive_inframe_insertion	Exon 1 of 12	NP_077308.1	P46736-1
BRCC3	NM_001242640.2		c.27_35dupGCAGGCGGT	p.Val12_His13insGlnAlaVal	disruptive_inframe_insertion	Exon 1 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.27_35dupGCAGGCGGT	p.Val12_His13insGlnAlaVal	disruptive_inframe_insertion	Exon 1 of 11	ENSP00000328641.7	P46736-2
BRCC3	ENST00000369462.5	TSL:1	c.27_35dupGCAGGCGGT	p.Val12_His13insGlnAlaVal	disruptive_inframe_insertion	Exon 1 of 12	ENSP00000358474.1	P46736-1
BRCC3	ENST00000340647.8	TSL:2	c.27_35dupGCAGGCGGT	p.Val12_His13insGlnAlaVal	disruptive_inframe_insertion	Exon 1 of 11	ENSP00000344103.4	P46736-3

Frequencies

GnomAD3 genomes

AF:

0.0000979

AC:

AN:

112374

Hom.:

Cov.:

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:

0.00252

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000754

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000141

AC:

AN:

163208

AF XY:

0.000112

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000799

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000424

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000191

AC:

209

AN:

1091549

Hom.:

Cov.:

AF XY:

0.000232

AC XY:

AN XY:

358241

show subpopulations

African (AFR)

AF:

0.0000380

AC:

AN:

26289

American (AMR)

AF:

0.0000291

AC:

AN:

34422

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19262

East Asian (EAS)

AF:

0.000868

AC:

AN:

29937

South Asian (SAS)

AF:

0.00127

AC:

AN:

52945

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39826

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4113

European-Non Finnish (NFE)

AF:

0.000124

AC:

104

AN:

838900

Other (OTH)

AF:

0.000218

AC:

AN:

45855

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

AF:

0.0000979

AC:

AN:

112416

Hom.:

Cov.:

AF XY:

0.000115

AC XY:

AN XY:

34668

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31078

American (AMR)

AF:

0.00

AC:

AN:

10794

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2647

East Asian (EAS)

AF:

0.00

AC:

AN:

3542

South Asian (SAS)

AF:

0.00253

AC:

AN:

2771

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6148

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0000755

AC:

AN:

53014

Other (OTH)

AF:

0.00

AC:

AN:

1533

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.539

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.6

Mutation Taster

=70/30

polymorphism

(source)

Splicing

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

Publications

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X-155071541-TGGTGCAGGC-TGGTGCAGGCGGTGCAGGC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over