7-2539223-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_152743.4(BRAT1):c.1726G>A(p.Gly576Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,610,692 control chromosomes in the GnomAD database, including 200 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G576A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.011 ( 17 hom., cov: 33)

Exomes 𝑓: 0.014 ( 183 hom. )

Consequence

BRAT1
NM_152743.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.03

Publications

7 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=0.00877741).

BP6

Variant 7-2539223-C-T is Benign according to our data. Variant chr7-2539223-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 472954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0113 (1724/152332) while in subpopulation NFE AF = 0.0163 (1108/68034). AF 95% confidence interval is 0.0155. There are 17 homozygotes in GnomAd4. There are 832 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAT1	NM_152743.4 link	c.1726G>A	p.Gly576Ser	missense_variant	Exon 13 of 14	ENST00000340611.9	NP_689956.2	Q6PJG6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAT1	ENST00000340611.9 link	c.1726G>A	p.Gly576Ser	missense_variant	Exon 13 of 14	1	NM_152743.4	ENSP00000339637.4		Q6PJG6-1

Frequencies

GnomAD3 genomes

AF:

0.0113

AC:

1725

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00275

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.0137

Gnomad ASJ

AF:

0.0167

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00579

Gnomad FIN

AF:

0.0159

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0163

Gnomad OTH

AF:

0.0125

GnomAD2 exomes

AF:

0.0115

AC:

2828

AN:

244884

AF XY:

0.0122

show subpopulations

Gnomad AFR exome

AF:

0.00281

Gnomad AMR exome

AF:

0.00877

Gnomad ASJ exome

AF:

0.0163

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0155

Gnomad NFE exome

AF:

0.0155

Gnomad OTH exome

AF:

0.0129

GnomAD4 exome

AF:

0.0143

AC:

20926

AN:

1458360

Hom.:

183

Cov.:

AF XY:

0.0142

AC XY:

10301

AN XY:

725374

show subpopulations

African (AFR)

AF:

0.00227

AC:

AN:

33414

American (AMR)

AF:

0.00868

AC:

388

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.0158

AC:

413

AN:

26110

East Asian (EAS)

AF:

0.000101

AC:

AN:

39686

South Asian (SAS)

AF:

0.00782

AC:

674

AN:

86150

European-Finnish (FIN)

AF:

0.0154

AC:

804

AN:

52120

Middle Eastern (MID)

AF:

0.00632

AC:

AN:

4430

European-Non Finnish (NFE)

AF:

0.0159

AC:

17717

AN:

1111564

Other (OTH)

AF:

0.0137

AC:

822

AN:

60192

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

1280

2560

3839

5119

6399

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

658

1316

1974

2632

3290

<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:

0.0113

AC:

1724

AN:

152332

Hom.:

Cov.:

AF XY:

0.0112

AC XY:

832

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00274

AC:

114

AN:

41578

American (AMR)

AF:

0.0137

AC:

209

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0167

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00579

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0159

AC:

169

AN:

10616

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0163

AC:

1108

AN:

68034

Other (OTH)

AF:

0.0123

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

184

275

367

459

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.0134

Hom.:

Bravo

AF:

0.0109

TwinsUK

AF:

0.0132

AC:

ALSPAC

AF:

0.0182

AC:

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.0185

AC:

159

ExAC

AF:

0.0114

AC:

1386

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0147

EpiControl

AF:

0.0148

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Sep 16, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neonatal-onset encephalopathy with rigidity and seizures

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neonatal-onset encephalopathy with rigidity and seizures;C4748032:Neurodevelopmental disorder with cerebellar atrophy and with or without seizures

Benign:1

Oct 05, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jul 31, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.00065

Eigen

Benign

-0.069

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.83

MetaRNN

Benign

0.0088

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

PhyloP100

2.0

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.51

REVEL

Benign

0.098

Sift

Benign

0.44

Sift4G

Benign

1.0

Polyphen

1.0

Vest4

0.20

MPC

0.29

ClinPred

0.015

GERP RS

4.9

Varity_R

0.061

gMVP

0.15

Mutation Taster

=98/2

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over