12-111644248-C-T

Variant summary

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

The NM_006768.5(BRAP):c.1730G>A(p.Gly577Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,376 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000055 (1 hom.)
• Consequence: BRAP NM_006768.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.668

Genes affected

BRAP (HGNC:1099): (BRCA1 associated protein) The protein encoded by this gene was identified by its ability to bind to the nuclear localization signal of BRCA1 and other proteins. It is a cytoplasmic protein which may regulate nuclear targeting by retaining proteins with a nuclear localization signal in the cytoplasm. [provided by RefSeq, Jul 2008]

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=0.08073297).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRAP	NM_006768.5	c.1730G>A	p.Gly577Asp	missense_variant	12/12	ENST00000419234.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRAP	ENST00000419234.9	c.1730G>A	p.Gly577Asp	missense_variant	12/12	1	NM_006768.5	P1
BRAP	ENST00000327551.6	c.1640G>A	p.Gly547Asp	missense_variant	12/12	1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251018 Hom.: 1 AF XY: 0.00 AC XY: 0 AN XY: 135736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461376 Hom.: 1 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727012

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000134

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 02, 2023

The c.1730G>A (p.G577D) alteration is located in exon 12 (coding exon 12) of the BRAP gene. This alteration results from a G to A substitution at nucleotide position 1730, causing the glycine (G) at amino acid position 577 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	9.9
Dann	Benign	0.95
DEOGEN2	Benign	0.34	T;T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.56	T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.081	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.38	N;N
REVEL	Benign	0.065
Sift	Benign	0.36	T;T
Sift4G	Benign	0.51	T;T
Polyphen		0.079	B;.
Vest4		0.12
MutPred		0.29		Gain of catalytic residue at G576 (P = 0.0017);.;
MVP		0.49
MPC		0.17
ClinPred		0.048	T
GERP RS		3.9
Varity_R		0.038
gMVP		0.40

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: rs1332115393; hg19: chr12-112082052;