X-155116702-A-G

Position:

• chrX-155116702-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001018055.3(BRCC3):​c.681-9A>G variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001907
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.641

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

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 20 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCC3	NM_001018055.3	c.681-9A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000330045.12	NP_001018065.1
BRCC3	NM_001242640.2	c.684-9A>G		splice_polypyrimidine_tract_variant, intron_variant			NP_001229569.1
BRCC3	NM_024332.4	c.756-9A>G		splice_polypyrimidine_tract_variant, intron_variant			NP_077308.1
BRCC3	XM_005274751.5	c.759-9A>G		splice_polypyrimidine_tract_variant, intron_variant			XP_005274808.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCC3	ENST00000330045.12	c.681-9A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001018055.3	ENSP00000328641	P3

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1350 AN: 112246 Hom.: 20 Cov.: 23 AF XY: 0.0101 AC XY: 346 AN XY: 34418

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

GnomAD3 exomes AF: 0.00333 AC: 458 AN: 137596 Hom.: 4 AF XY: 0.00206 AC XY: 84 AN XY: 40838

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 SAS exome AF: 0.0000696

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

Gnomad4 AFR exome AF: 0.0342

Gnomad4 AMR exome AF: 0.00372

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000806

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000369

Gnomad4 OTH exome AF: 0.00308

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

Gnomad4 AFR AF: 0.0406

Gnomad4 AMR AF: 0.00706

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000939

Gnomad4 OTH AF: 0.0117

Alfa AF: 0.00471 Hom.: 25

Bravo AF: 0.0141

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.52
DANN	Benign	0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs140398462; hg19: chrX-154344977;