X-155078908-A-G

Variant names:

• chrX-155078908-A-G
• rs190280980
• NM_001018055.3:c.403+205A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001018055.3(BRCC3):​c.403+205A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00561 in 353,424 control chromosomes in the GnomAD database, including 13 homozygotes. There are 547 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0047 (2 hom., 148 hem., cov: 23)
  • Exomes 𝑓: 0.0060 (11 hom. 399 hem.)
• Consequence: BRCC3 NM_001018055.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.291
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant X-155078908-A-G is Benign according to our data. Variant chrX-155078908-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 223603.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 530 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCC3	NM_001018055.3	MANE Select	c.403+205A>G		intron	N/A	NP_001018065.1	P46736-2
	BRCC3	NM_024332.4		c.403+205A>G		intron	N/A	NP_077308.1	P46736-1
	BRCC3	NM_001242640.2		c.406+205A>G		intron	N/A	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.403+205A>G		intron	N/A	ENSP00000328641.7	P46736-2
	BRCC3	ENST00000369462.5	TSL:1	c.403+205A>G		intron	N/A	ENSP00000358474.1	P46736-1
	BRCC3	ENST00000399026.1	TSL:5	c.*161A>G		3_prime_UTR	Exon 3 of 3	ENSP00000381988.1	A0A0A0MS96

Frequencies

GnomAD3 genomes AF: 0.00472 AC: 530 AN: 112303 Hom.: 2 Cov.: 23

Gnomad AFR AF: 0.00136

Gnomad AMI AF: 0.0116

Gnomad AMR AF: 0.00132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00146

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00863

Gnomad OTH AF: 0.00132

GnomAD4 exome AF: 0.00602 AC: 1452 AN: 241070 Hom.: 11 Cov.: 2 AF XY: 0.00619 AC XY: 399 AN XY: 64446

African (AFR) AF: 0.00153 AC: 10 AN: 6550

American (AMR) AF: 0.000979 AC: 8 AN: 8173

Ashkenazi Jewish (ASJ) AF: 0.000129 AC: 1 AN: 7774

East Asian (EAS) AF: 0.00 AC: 0 AN: 17399

South Asian (SAS) AF: 0.00299 AC: 40 AN: 13371

European-Finnish (FIN) AF: 0.000825 AC: 18 AN: 21824

Middle Eastern (MID) AF: 0.000933 AC: 1 AN: 1072

European-Non Finnish (NFE) AF: 0.00855 AC: 1281 AN: 149867

Other (OTH) AF: 0.00618 AC: 93 AN: 15040

GnomAD4 genome AF: 0.00472 AC: 530 AN: 112354 Hom.: 2 Cov.: 23 AF XY: 0.00429 AC XY: 148 AN XY: 34502

African (AFR) AF: 0.00136 AC: 42 AN: 30922

American (AMR) AF: 0.00132 AC: 14 AN: 10619

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2659

East Asian (EAS) AF: 0.00 AC: 0 AN: 3608

South Asian (SAS) AF: 0.00147 AC: 4 AN: 2729

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.00863 AC: 460 AN: 53284

Other (OTH) AF: 0.00131 AC: 2 AN: 1529

Alfa AF: 0.00551 Hom.: 32

Bravo AF: 0.00463

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.4
DANN	Benign	0.89
PhyloP100		0.29
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs190280980; hg19: chrX-154307183;