rs145509776

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1PM2BP4_ModerateBP6

The NM_152743.4(BRAT1):c.1564G>C(p.Glu522Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000986 in 1,581,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E522K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

BRAT1
NM_152743.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 5.86

Variant links:

Genes affected

BRAT1 (HGNC:21701): (BRCA1 associated ATM activator 1) The protein encoded by this ubiquitously expressed gene interacts with the tumor suppressing BRCA1 (breast cancer 1) protein and and the ATM (ataxia telangiectasia mutated) protein. ATM is thought to be a master controller of cell cycle checkpoint signalling pathways that are required for cellular responses to DNA damage such as double-strand breaks that are induced by ionizing radiation and complexes with BRCA1 in the multi-protein complex BASC (BRAC1-associated genome surveillance complex). The protein encoded by this gene is thought to play a role in the DNA damage pathway regulated by BRCA1 and ATM. [provided by RefSeq, Mar 2012]

BRAT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_152743.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13021135).

BP6

Variant 7-2539577-C-G is Benign according to our data. Variant chr7-2539577-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 540190.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRAT1	NM_152743.4 linkuse as main transcript	c.1564G>C	p.Glu522Gln	missense_variant	12/14	ENST00000340611.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRAT1	ENST00000340611.9 linkuse as main transcript	c.1564G>C	p.Glu522Gln	missense_variant	12/14	1	NM_152743.4	P1	Q6PJG6-1

Frequencies

GnomAD3 genomes

AF:

0.000513

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00179

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000140

AC:

AN:

200214

Hom.:

AF XY:

0.000111

AC XY:

AN XY:

107708

show subpopulations

Gnomad AFR exome

AF:

0.00212

Gnomad AMR exome

AF:

0.0000665

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:

0.0000116

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000553

AC:

AN:

1429300

Hom.:

Cov.:

AF XY:

0.0000565

AC XY:

AN XY:

708078

show subpopulations

Gnomad4 AFR exome

AF:

0.00200

Gnomad4 AMR exome

AF:

0.000123

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:

9.13e-7

Gnomad4 OTH exome

AF:

0.000135

GnomAD4 genome

AF:

0.000506

AC:

AN:

152282

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00178

Gnomad4 AMR

AF:

0.000131

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:

0.000608

Hom.:

Bravo

AF:

0.000544

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000158

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 10, 2023

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 26947546, 32211283) -

BRAT1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 07, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Neonatal-onset encephalopathy with rigidity and seizures

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Benign

0.00031

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.83

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.28

MutationAssessor

Uncertain

2.4

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.58

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.013

Polyphen

1.0

Vest4

0.90

MVP

0.63

MPC

0.32

ClinPred

0.10

GERP RS

4.7

Varity_R

0.68

gMVP

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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