Genetic Variant BRAP:p.Met441Ile (chr12-111650031-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_006768.5(BRAP):c.1323G>A(p.Met441Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000936 in 1,602,686 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M441V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000097 ( 0 hom. )

Consequence

BRAP
NM_006768.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.36

Variant links:

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 links:

LOC124903020 (HGNC:):

LOC124903020 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAP	NM_006768.5 link	c.1323G>A	p.Met441Ile	missense_variant	Exon 11 of 12	ENST00000419234.9	NP_006759.3	Q7Z569-1Q59H81

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BRAP	ENST00000419234.9 link	c.1323G>A	p.Met441Ile	missense_variant	Exon 11 of 12	1	NM_006768.5	ENSP00000403524.3	Q7Z569-1
BRAP	ENST00000327551.6 link	c.1233G>A	p.Met411Ile	missense_variant	Exon 11 of 12	1		ENSP00000330813.5	J3KNN7
BRAP	ENST00000547043.1 link	n.1227G>A		non_coding_transcript_exon_variant	Exon 7 of 8	3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

250680

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135542

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.00

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000965

AC:

AN:

1450530

Hom.:

Cov.:

AF XY:

0.00000692

AC XY:

AN XY:

722220

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

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:

0.0000118

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 24, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1323G>A (p.M441I) alteration is located in exon 11 (coding exon 11) of the BRAP gene. This alteration results from a G to A substitution at nucleotide position 1323, causing the methionine (M) at amino acid position 441 to be replaced by an isoleucine (I). 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

0.93

BayesDel_addAF

Benign

-0.040

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

T;T

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.0086

MetaRNN

Uncertain

0.54

D;D

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.8

L;.

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-0.63

N;N

REVEL

Benign

0.22

Sift

Benign

0.13

T;T

Sift4G

Benign

0.19

T;T

Polyphen

0.28

B;.

Vest4

0.72

MutPred

0.36

Gain of methylation at K442 (P = 0.0457);.;

MVP

0.57

MPC

0.15

ClinPred

0.22

GERP RS

5.7

Varity_R

0.25

gMVP

0.55

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over