chr3-52404490-C-CGTCATCCTCATA

Variant names:

• chr3-52404490-C-CGTCATCCTCATA
• rs776606194
• NM_004656.4:c.1201_1212dupTATGAGGATGAC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_004656.4(BAP1):​c.1201_1212dupTATGAGGATGAC​(p.Asp404_Glu405insTyrGluAspAsp) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D404D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BAP1 NM_004656.4 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -5.65
• Publications: 0 publications found

Genes affected

BAP1 (HGNC:950): (BRCA1 associated protein 1) This gene belongs to the ubiquitin C-terminal hydrolase subfamily of deubiquitinating enzymes that are involved in the removal of ubiquitin from proteins. The encoded enzyme binds to the breast cancer type 1 susceptibility protein (BRCA1) via the RING finger domain of the latter and acts as a tumor suppressor. In addition, the enzyme may be involved in regulation of transcription, regulation of cell cycle and growth, response to DNA damage and chromatin dynamics. Germline mutations in this gene may be associated with tumor predisposition syndrome (TPDS), which involves increased risk of cancers including malignant mesothelioma, uveal melanoma and cutaneous melanoma. [provided by RefSeq, May 2013]

BAP1 Gene-Disease associations (from GenCC):

• BAP1-related tumor predisposition syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, G2P, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Kury-Isidor syndrome

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, G2P
• renal cell carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BAP1	NM_004656.4	c.1201_1212dupTATGAGGATGAC	p.Asp404_Glu405insTyrGluAspAsp	conservative_inframe_insertion	Exon 12 of 17	ENST00000460680.6	NP_004647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BAP1	ENST00000460680.6	c.1201_1212dupTATGAGGATGAC	p.Asp404_Glu405insTyrGluAspAsp	conservative_inframe_insertion	Exon 12 of 17	1	NM_004656.4	ENSP00000417132.1
BAP1	ENST00000296288.9	c.1147_1158dupTATGAGGATGAC	p.Asp386_Glu387insTyrGluAspAsp	conservative_inframe_insertion	Exon 12 of 17	5		ENSP00000296288.5
BAP1	ENST00000490804.1	n.629_640dupTATGAGGATGAC		non_coding_transcript_exon_variant	Exon 2 of 3	2
BAP1	ENST00000469613.5	c.-27_-16dupTATGAGGATGAC		upstream_gene_variant		1		ENSP00000418320.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Oct 09, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1201_1212dup12 variant (also known as p.Y401_D404dup), located in coding exon 12 of the BAP1 gene, results from an in-frame duplication of 12 nucleotides at nucleotide positions 1201 to 1212. This results in the duplication of 4 extra residues (YEDD) between codons 401 and 404. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-5.7

Splicing

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

Other links and lift over

dbSNP: rs776606194; hg19: chr3-52438506;