rs146546197

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_152743.4(BRAT1):c.826G>A(p.Asp276Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00018 in 1,607,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00068 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

BRAT1
NM_152743.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 0.546

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.006489545).

BP6

Variant 7-2543301-C-T is Benign according to our data. Variant chr7-2543301-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 472981.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRAT1	NM_152743.4 linkuse as main transcript	c.826G>A	p.Asp276Asn	missense_variant	6/14	ENST00000340611.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRAT1	ENST00000340611.9 linkuse as main transcript	c.826G>A	p.Asp276Asn	missense_variant	6/14	1	NM_152743.4	P1	Q6PJG6-1

Frequencies

GnomAD3 genomes

AF:

0.000684

AC:

104

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00224

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

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:

0.00

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000276

AC:

AN:

246102

Hom.:

AF XY:

0.000187

AC XY:

AN XY:

133414

show subpopulations

Gnomad AFR exome

AF:

0.00230

Gnomad AMR exome

AF:

0.000626

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000224

Gnomad SAS exome

AF:

0.0000332

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000450

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000128

AC:

186

AN:

1455478

Hom.:

Cov.:

AF XY:

0.000115

AC XY:

AN XY:

723528

show subpopulations

Gnomad4 AFR exome

AF:

0.00216

Gnomad4 AMR exome

AF:

0.000637

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000203

Gnomad4 SAS exome

AF:

0.0000233

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000478

Gnomad4 OTH exome

AF:

0.000333

GnomAD4 genome

AF:

0.000683

AC:

104

AN:

152270

Hom.:

Cov.:

AF XY:

0.000752

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00224

Gnomad4 AMR

AF:

0.000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.0000898

Hom.:

Bravo

AF:

0.000782

ESP6500AA

AF:

0.00340

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000255

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Neonatal-onset encephalopathy with rigidity and seizures

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as VUS - 3C. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to asparagine (exon 6). (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD v3 <0.01 for a recessive condition (98 heterozygotes, 0 homozygotes). (P) 0504 - Same amino acid change has been observed in mammals. (B) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0806 - Moderate previous evidence of neutrality in unrelated individuals. This variant has been reported once a likely benign (ClinVar). This variant was also observed in a patient with atypical peroxisomal biogenesis disorder, but an alternative diagnosis in PEX6 was found (PMID: 26870756). (B) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 26, 2022

Observed in individual with ataxia, spastic paraparesis, leukodystrophy and cognitive decline who also harbored a second BRAT1 variant in the compound heterozygous state; however, this individual also harbored a homozygous variant in the PEX16 gene which was considered by the authors to be disease causative (Bacino et. al., 2016).; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26870756) -

BRAT1-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 06, 2022

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). -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2021

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.65

Cadd

Benign

Dann

Benign

0.97

DEOGEN2

Benign

0.0033

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.098

LIST_S2

Benign

0.63

M_CAP

Benign

0.024

MetaRNN

Benign

0.0065

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.1

MutationTaster

Benign

1.0

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.90

REVEL

Benign

0.054

Sift

Benign

0.16

Sift4G

Benign

0.17

Polyphen

0.0010

Vest4

0.12

MVP

0.33

MPC

0.045

ClinPred

0.0077

GERP RS

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.038

gMVP

0.083

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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