X-155071541-TGGTGCAGGC-TGGTGCAGGCGGTGCAGGCGGTGCAGGC

Variant names:

• chrX-155071541-T-TGGTGCAGGCGGTGCAGGC
• rs782702164
• NM_001018055.3:c.18_35dupGCAGGCGGTGCAGGCGGT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM4 BS2

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. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.55
• Publications: 0 publications found

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]

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]

ACMG classification

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 GnomAdExome4 at 23 XL,AD 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCC3	NM_001018055.3	MANE Select	c.18_35dupGCAGGCGGTGCAGGCGGT	p.Val12_His13insGlnAlaValGlnAlaVal	disruptive_inframe_insertion	Exon 1 of 11	NP_001018065.1	P46736-2
	BRCC3	NM_024332.4		c.18_35dupGCAGGCGGTGCAGGCGGT	p.Val12_His13insGlnAlaValGlnAlaVal	disruptive_inframe_insertion	Exon 1 of 12	NP_077308.1	P46736-1
	BRCC3	NM_001242640.2		c.18_35dupGCAGGCGGTGCAGGCGGT	p.Val12_His13insGlnAlaValGlnAlaVal	disruptive_inframe_insertion	Exon 1 of 11	NP_001229569.1	P46736-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCC3	ENST00000330045.12	TSL:1 MANE Select	c.18_35dupGCAGGCGGTGCAGGCGGT	p.Val12_His13insGlnAlaValGlnAlaVal	disruptive_inframe_insertion	Exon 1 of 11	ENSP00000328641.7	P46736-2
	BRCC3	ENST00000369462.5	TSL:1	c.18_35dupGCAGGCGGTGCAGGCGGT	p.Val12_His13insGlnAlaValGlnAlaVal	disruptive_inframe_insertion	Exon 1 of 12	ENSP00000358474.1	P46736-1
	BRCC3	ENST00000340647.8	TSL:2	c.18_35dupGCAGGCGGTGCAGGCGGT	p.Val12_His13insGlnAlaValGlnAlaVal	disruptive_inframe_insertion	Exon 1 of 11	ENSP00000344103.4	P46736-3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000184 AC: 3 AN: 163208 AF XY: 0.0000374

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000141

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000211 AC: 23 AN: 1091549 Hom.: 0 Cov.: 31 AF XY: 0.0000279 AC XY: 10 AN XY: 358241

African (AFR) AF: 0.00 AC: 0 AN: 26289

American (AMR) AF: 0.00 AC: 0 AN: 34422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19262

East Asian (EAS) AF: 0.00 AC: 0 AN: 29937

South Asian (SAS) AF: 0.000227 AC: 12 AN: 52945

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39826

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4113

European-Non Finnish (NFE) AF: 0.0000107 AC: 9 AN: 838900

Other (OTH) AF: 0.0000436 AC: 2 AN: 45855

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6
Mutation Taster		=77/23	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs782702164; hg19: chrX-154299816;