chr7-2543273-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001350626.2(BRAT1):c.854G>A(p.Arg285Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0231 in 1,610,734 control chromosomes in the GnomAD database, including 2,175 homozygotes. 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R285W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.026 ( 272 hom., cov: 32)

Exomes 𝑓: 0.023 ( 1903 hom. )

Consequence

BRAT1
NM_001350626.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.94

Publications

13 publications found

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 Gene-Disease associations (from GenCC):

neonatal-onset encephalopathy with rigidity and seizures
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae)
neurodevelopmental disorder with cerebellar atrophy and with or without seizures
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics

BRAT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004017681).

BP6

Variant 7-2543273-C-T is Benign according to our data. Variant chr7-2543273-C-T is described in ClinVar as Benign. ClinVar VariationId is 472982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.258 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001350626.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BRAT1	NM_152743.4	MANE Select	c.854G>A	p.Arg285Gln	missense	Exon 6 of 14	NP_689956.2
BRAT1	NM_001350626.2		c.854G>A	p.Arg285Gln	missense	Exon 6 of 14	NP_001337555.1
BRAT1	NM_001350627.2		c.329G>A	p.Arg110Gln	missense	Exon 5 of 13	NP_001337556.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BRAT1	ENST00000340611.9	TSL:1 MANE Select	c.854G>A	p.Arg285Gln	missense	Exon 6 of 14	ENSP00000339637.4
BRAT1	ENST00000890463.1		c.854G>A	p.Arg285Gln	missense	Exon 6 of 16	ENSP00000560522.1
BRAT1	ENST00000917322.1		c.851G>A	p.Arg284Gln	missense	Exon 6 of 16	ENSP00000587381.1

Frequencies

GnomAD3 genomes

AF:

0.0262

AC:

3985

AN:

152128

Hom.:

277

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00299

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0397

Gnomad ASJ

AF:

0.0179

Gnomad EAS

AF:

0.271

Gnomad SAS

AF:

0.110

Gnomad FIN

AF:

0.0515

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00969

Gnomad OTH

AF:

0.0263

GnomAD2 exomes

AF:

0.0488

AC:

12097

AN:

247920

AF XY:

0.0497

show subpopulations

Gnomad AFR exome

AF:

0.00217

Gnomad AMR exome

AF:

0.0416

Gnomad ASJ exome

AF:

0.0207

Gnomad EAS exome

AF:

0.276

Gnomad FIN exome

AF:

0.0526

Gnomad NFE exome

AF:

0.0111

Gnomad OTH exome

AF:

0.0348

GnomAD4 exome

AF:

0.0227

AC:

33158

AN:

1458488

Hom.:

1903

Cov.:

AF XY:

0.0249

AC XY:

18032

AN XY:

725378

show subpopulations

African (AFR)

AF:

0.00237

AC:

AN:

33388

American (AMR)

AF:

0.0419

AC:

1857

AN:

44316

Ashkenazi Jewish (ASJ)

AF:

0.0205

AC:

534

AN:

26054

East Asian (EAS)

AF:

0.229

AC:

9010

AN:

39390

South Asian (SAS)

AF:

0.0953

AC:

8177

AN:

85846

European-Finnish (FIN)

AF:

0.0497

AC:

2615

AN:

52644

Middle Eastern (MID)

AF:

0.0395

AC:

227

AN:

5742

European-Non Finnish (NFE)

AF:

0.00770

AC:

8553

AN:

1110868

Other (OTH)

AF:

0.0350

AC:

2106

AN:

60240

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

1403

2805

4208

5610

7013

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

512

1024

1536

2048

2560

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0261

AC:

3973

AN:

152246

Hom.:

272

Cov.:

AF XY:

0.0309

AC XY:

2303

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00298

AC:

124

AN:

41560

American (AMR)

AF:

0.0397

AC:

608

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0179

AC:

AN:

3472

East Asian (EAS)

AF:

0.269

AC:

1388

AN:

5154

South Asian (SAS)

AF:

0.109

AC:

528

AN:

4824

European-Finnish (FIN)

AF:

0.0515

AC:

546

AN:

10606

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00967

AC:

658

AN:

68014

Other (OTH)

AF:

0.0260

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

175

350

526

701

876

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0203

Hom.:

589

Bravo

AF:

0.0236

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00649

AC:

ESP6500AA

AF:

0.00250

AC:

ESP6500EA

AF:

0.00965

AC:

ExAC

AF:

0.0488

AC:

5919

Asia WGS

AF:

0.144

AC:

500

AN:

3478

EpiCase

AF:

0.00988

EpiControl

AF:

0.0109

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Neonatal-onset encephalopathy with rigidity and seizures (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.55

CADD

Benign

0.072

(source)

DANN

Benign

0.52

DEOGEN2

Benign

0.00092

Eigen

Benign

-2.2

Eigen_PC

Benign

-2.2

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.22

MetaRNN

Benign

0.0040

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.40

PhyloP100

-1.9

PrimateAI

Benign

0.27

PROVEAN

Benign

0.31

REVEL

Benign

0.21

Sift

Benign

1.0

Sift4G

Benign

0.69

Polyphen

0.0

Vest4

0.021

MPC

0.050

ClinPred

0.0064

GERP RS

-9.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.012

gMVP

0.036

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over