X-155072340-C-T

Variant names:

• chrX-155072340-C-T
• NM_001018055.3:c.137C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001018055.3(BRCC3):​c.137C>T​(p.Thr46Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000093 in 1,075,446 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.3e-7 (0 hom. 0 hem.)
• Consequence: BRCC3 NM_001018055.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0220

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16738701).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCC3	NM_001018055.3	c.137C>T	p.Thr46Ile	missense_variant	Exon 2 of 11	ENST00000330045.12	NP_001018065.1
BRCC3	NM_024332.4	c.137C>T	p.Thr46Ile	missense_variant	Exon 2 of 12		NP_077308.1
BRCC3	NM_001242640.2	c.137C>T	p.Thr46Ile	missense_variant	Exon 2 of 11		NP_001229569.1
BRCC3	XM_005274751.5	c.137C>T	p.Thr46Ile	missense_variant	Exon 2 of 12		XP_005274808.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCC3	ENST00000330045.12	c.137C>T	p.Thr46Ile	missense_variant	Exon 2 of 11	1	NM_001018055.3	ENSP00000328641.7

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.30e-7 AC: 1 AN: 1075446 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 342756

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000121

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.13	.;.;.;T;.;.
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.23	T;T;T;T;T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.13	T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.3	L;L;L;L;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.11	N;N;N;N;.;.
REVEL	Benign	0.059
Sift	Benign	0.63	T;T;T;T;.;.
Sift4G	Benign	0.45	T;T;T;T;T;T
Polyphen		0.0	B;B;.;B;.;.
Vest4		0.13
MutPred		0.49		Loss of phosphorylation at T46 (P = 0.0096);Loss of phosphorylation at T46 (P = 0.0096);Loss of phosphorylation at T46 (P = 0.0096);Loss of phosphorylation at T46 (P = 0.0096);Loss of phosphorylation at T46 (P = 0.0096);Loss of phosphorylation at T46 (P = 0.0096);
MVP		0.82
MPC		1.3
ClinPred		0.062	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.070
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-154300615;