rs140398462

Variant names:

• chrX-155116702-A-G
• rs140398462
• NM_001018055.3:c.681-9A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001018055.3(BRCC3):​c.681-9A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00216 in 1,166,423 control chromosomes in the GnomAD database, including 34 homozygotes. There are 640 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (20 hom., 348 hem., cov: 23)
  • Exomes 𝑓: 0.0011 (14 hom. 292 hem.)
• Consequence: BRCC3 NM_001018055.3 intron
• Scores: Splicing: ADA: 0.00001907
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.641
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant X-155116702-A-G is Benign according to our data. Variant chrX-155116702-A-G is described in ClinVar as Benign. ClinVar VariationId is 710187.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.012 (1352/112300) while in subpopulation AFR AF = 0.0406 (1254/30914). AF 95% confidence interval is 0.0387. There are 20 homozygotes in GnomAd4. There are 348 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1352 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.681-9A>G		intron	N/A	NP_001018065.1	P46736-2
	BRCC3	NM_024332.4		c.756-9A>G		intron	N/A	NP_077308.1	P46736-1
	BRCC3	NM_001242640.2		c.684-9A>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.681-9A>G		intron	N/A	ENSP00000328641.7	P46736-2
	BRCC3	ENST00000369462.5	TSL:1	c.756-9A>G		intron	N/A	ENSP00000358474.1	P46736-1
	BRCC3	ENST00000340647.8	TSL:2	c.684-9A>G		intron	N/A	ENSP00000344103.4	P46736-3

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1350 AN: 112246 Hom.: 20 Cov.: 23

Gnomad AFR AF: 0.0406

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00707

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: 0.0000939

Gnomad OTH AF: 0.0119

GnomAD2 exomes AF: 0.00333 AC: 458 AN: 137596 AF XY: 0.00206

Gnomad AFR exome AF: 0.0415

Gnomad AMR exome AF: 0.00309

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000347

Gnomad OTH exome AF: 0.00139

GnomAD4 exome AF: 0.00110 AC: 1162 AN: 1054123 Hom.: 14 Cov.: 24 AF XY: 0.000873 AC XY: 292 AN XY: 334429

African (AFR) AF: 0.0342 AC: 872 AN: 25510

American (AMR) AF: 0.00372 AC: 116 AN: 31171

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18694

East Asian (EAS) AF: 0.00 AC: 0 AN: 29061

South Asian (SAS) AF: 0.0000806 AC: 4 AN: 49637

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38933

Middle Eastern (MID) AF: 0.000740 AC: 3 AN: 4056

European-Non Finnish (NFE) AF: 0.0000369 AC: 30 AN: 812565

Other (OTH) AF: 0.00308 AC: 137 AN: 44496

GnomAD4 genome AF: 0.0120 AC: 1352 AN: 112300 Hom.: 20 Cov.: 23 AF XY: 0.0101 AC XY: 348 AN XY: 34482

African (AFR) AF: 0.0406 AC: 1254 AN: 30914

American (AMR) AF: 0.00706 AC: 75 AN: 10628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3577

South Asian (SAS) AF: 0.00 AC: 0 AN: 2721

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6117

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0000939 AC: 5 AN: 53254

Other (OTH) AF: 0.0117 AC: 18 AN: 1533

Alfa AF: 0.0156 Hom.: 219

Bravo AF: 0.0141

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.52
DANN	Benign	0.61
PhyloP100		-0.64
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000019
dbscSNV1_RF	Benign	0.0
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: rs140398462; hg19: chrX-154344977;