rs869312530

Variant names:

• chrX-155071734-T-C
• rs869312530
• NM_001018055.3:c.123+84T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001018055.3(BRCC3):​c.123+84T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,063,062 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 41 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.000063 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.00012 (0 hom. 40 hem.)
• Consequence: BRCC3 NM_001018055.3 intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.946
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant X-155071734-T-C is Benign according to our data. Variant chrX-155071734-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 223602.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 7 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.123+84T>C		intron	N/A	NP_001018065.1	P46736-2
	BRCC3	NM_024332.4		c.123+84T>C		intron	N/A	NP_077308.1	P46736-1
	BRCC3	NM_001242640.2		c.123+84T>C		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.123+84T>C		intron	N/A	ENSP00000328641.7	P46736-2
	BRCC3	ENST00000369462.5	TSL:1	c.123+84T>C		intron	N/A	ENSP00000358474.1	P46736-1
	BRCC3	ENST00000340647.8	TSL:2	c.123+84T>C		intron	N/A	ENSP00000344103.4	P46736-3

Frequencies

GnomAD3 genomes AF: 0.0000627 AC: 7 AN: 111684 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000940

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

GnomAD4 exome AF: 0.000122 AC: 116 AN: 951378 Hom.: 0 AF XY: 0.000155 AC XY: 40 AN XY: 258424

African (AFR) AF: 0.0000434 AC: 1 AN: 23048

American (AMR) AF: 0.0000375 AC: 1 AN: 26676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16848

East Asian (EAS) AF: 0.00 AC: 0 AN: 26602

South Asian (SAS) AF: 0.00 AC: 0 AN: 45288

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36729

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3717

European-Non Finnish (NFE) AF: 0.000150 AC: 110 AN: 731715

Other (OTH) AF: 0.0000981 AC: 4 AN: 40755

GnomAD4 genome AF: 0.0000627 AC: 7 AN: 111684 Hom.: 0 Cov.: 23 AF XY: 0.0000295 AC XY: 1 AN XY: 33846

African (AFR) AF: 0.0000326 AC: 1 AN: 30659

American (AMR) AF: 0.0000940 AC: 1 AN: 10639

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2656

East Asian (EAS) AF: 0.00 AC: 0 AN: 3549

South Asian (SAS) AF: 0.00 AC: 0 AN: 2637

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6095

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000943 AC: 5 AN: 53026

Other (OTH) AF: 0.00 AC: 0 AN: 1502

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	8.7
DANN	Benign	0.84
PhyloP100		0.95
PromoterAI		0.10	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs869312530; hg19: chrX-154300009;