rs576538858

chr3-52403737-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_004656.4(BAP1):c.1408G>A(p.Gly470Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000415 in 1,614,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G470A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: BAP1 NM_004656.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3 O:2
• Conservation: PhyloP100: 3.47

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• PP2: Missense variant where missense usually causes diseases, BAP1
• BP4: Computational evidence support a benign effect (MetaRNN=0.07346314).
• BP6: Variant 3-52403737-C-T is Benign according to our data. Variant chr3-52403737-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 133663.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4, not_provided=2}. Variant chr3-52403737-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BAP1	NM_004656.4	c.1408G>A	p.Gly470Arg	missense_variant	13/17	ENST00000460680.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BAP1	ENST00000460680.6	c.1408G>A	p.Gly470Arg	missense_variant	13/17	1	NM_004656.4	P1
BAP1	ENST00000469613.5	c.119+64G>A		intron_variant		1
BAP1	ENST00000296288.9	c.1354G>A	p.Gly452Arg	missense_variant	13/17	5
BAP1	ENST00000490804.1	n.836G>A		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152112 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

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: 0.0000441

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.0000716 AC: 18 AN: 251298 Hom.: 0 AF XY: 0.0000810 AC XY: 11 AN XY: 135872

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.0000335 AC: 49 AN: 1461794 Hom.: 0 Cov.: 32 AF XY: 0.0000303 AC XY: 22 AN XY: 727200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000207

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152230 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74434

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.0000499 Hom.: 0

Bravo AF: 0.000408

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:3 Other:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Aug 31, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 04, 2023	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 11, 2021	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with thyroid cancer and healthy individuals under age 50 undergoing whole genome sequencing (Bodian 2014, Yehia 2018); This variant is associated with the following publications: (PMID: 30480620, 24728327, 29684080) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 08, 2023	In the published literature, this variant has been reported in an individual with thyroid cancer (PMID: 29684080 (2018)), and in healthy individuals under the age of 50 (PMID: 24728327 (2014)). It has also been reported as a somatic variant in an individual with uveal melanoma (PMID: 30480620 (2019)). The frequency of this variant in the general population, 0.00023 (8/34582 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

BAP1-related tumor predisposition syndrome Uncertain:1 Other:1

not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Uncertain significance and reported on 10-22-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 470 of the BAP1 protein (p.Gly470Arg). This variant is present in population databases (rs576538858, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with BAP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 133663). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BAP1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	21
Dann	Benign	0.94
DEOGEN2	Benign	0.020	T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	0.080
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.073	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.080	N;N
REVEL	Benign	0.12
Sift	Benign	0.47	T;T
Sift4G	Benign	0.59	T;T
Polyphen		0.0010	B;.
Vest4		0.38
MutPred		0.23		Gain of solvent accessibility (P = 0.019);.;
MVP		0.65
MPC		0.45
ClinPred		0.047	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.033
gMVP		0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs576538858; hg19: chr3-52437753;