12-111658780-C-T

Position:

• chr12-111658780-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006768.5(BRAP):​c.1177G>A​(p.Gly393Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAP NM_006768.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.36

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]

BRAP (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.802

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRAP	NM_006768.5	c.1177G>A	p.Gly393Arg	missense_variant	9/12	ENST00000419234.9	NP_006759.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRAP	ENST00000419234.9	c.1177G>A	p.Gly393Arg	missense_variant	9/12	1	NM_006768.5	ENSP00000403524.3
BRAP	ENST00000327551.6	c.1087G>A	p.Gly363Arg	missense_variant	9/12	1		ENSP00000330813.5
BRAP	ENST00000547043.1	n.1081G>A		non_coding_transcript_exon_variant	5/8	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

Feb 28, 2024

The c.1177G>A (p.G393R) alteration is located in exon 9 (coding exon 9) of the BRAP gene. This alteration results from a G to A substitution at nucleotide position 1177, causing the glycine (G) at amino acid position 393 to be replaced by an arginine (R). 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	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;T
Eigen	Pathogenic	0.68
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.075	D
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.4	M;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.7	D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.79	P;.
Vest4		0.73
MutPred		0.40		Gain of catalytic residue at Q397 (P = 0.0071);.;
MVP		0.79
MPC		2.6
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.44
gMVP		0.70

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: rs1178512876; hg19: chr12-112096584;