rs749240175

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_152743.4(BRAT1):c.1313_1314delAG(p.Gln438ArgfsTer51) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000314 in 1,590,352 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

BRAT1
NM_152743.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 0.317

Publications

5 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: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-2541304-CCT-C is Pathogenic according to our data. Variant chr7-2541304-CCT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 472936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAT1	NM_152743.4 link	c.1313_1314delAG	p.Gln438ArgfsTer51	frameshift_variant	Exon 9 of 14	ENST00000340611.9	NP_689956.2	Q6PJG6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BRAT1	ENST00000340611.9 link	c.1313_1314delAG	p.Gln438ArgfsTer51	frameshift_variant	Exon 9 of 14	1	NM_152743.4	ENSP00000339637.4	Q6PJG6-1
BRAT1	ENST00000467558.5 link	n.1595_1596delAG		non_coding_transcript_exon_variant	Exon 7 of 10	5
BRAT1	ENST00000469750.5 link	n.2795_2796delAG		non_coding_transcript_exon_variant	Exon 7 of 11	2
BRAT1	ENST00000493232.5 link	n.2714_2715delAG		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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

GnomAD2 exomes

AF:

0.0000657

AC:

AN:

228138

AF XY:

0.0000560

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.000121

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000573

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000313

AC:

AN:

1438138

Hom.:

AF XY:

0.0000322

AC XY:

AN XY:

714770

show subpopulations

African (AFR)

AF:

0.0000904

AC:

AN:

33202

American (AMR)

AF:

0.0000926

AC:

AN:

43192

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24982

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39568

South Asian (SAS)

AF:

0.0000473

AC:

AN:

84498

European-Finnish (FIN)

AF:

0.0000232

AC:

AN:

43076

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5678

European-Non Finnish (NFE)

AF:

0.0000290

AC:

AN:

1104230

Other (OTH)

AF:

0.00

AC:

AN:

59712

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000328

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41450

American (AMR)

AF:

0.000196

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.0000302

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neonatal-onset encephalopathy with rigidity and seizures

Pathogenic:2

Apr 14, 2017

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Gln438Argfs*51) in the BRAT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRAT1 are known to be pathogenic (PMID: 22279524, 25500575). This variant is present in population databases (rs749240175, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with BRAT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 472936). For these reasons, this variant has been classified as Pathogenic. -

Neurodevelopmental disorder with cerebellar atrophy and with or without seizures

Pathogenic:2

Oct 14, 2021

HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

ACMG codes: PVS1, PM2, PP5 -

Oct 14, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: BRAT1 c.1313_1314delAG (p.Gln438ArgfsX51) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 6.6e-05 in 228138 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BRAT1 causing Neurodevelopmental Disorder With Cerebellar Atrophy And With Or Without Seizures, allowing no conclusion about variant significance. c.1313_1314delAG has been reported in the literature in a homozygous individual affected with Neurodevelopmental Disorder With Cerebellar Atrophy And With Or Without Seizures (Szymaska_2018). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 30786674). ClinVar contains an entry for this variant (Variation ID: 472936). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:2

Jun 23, 2023

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1, PS4, PM2_SUP -

Sep 11, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30786674, 31589614, 36209187, 35360849, 35620305, 31440721, 37344571) -

Inborn genetic diseases

Pathogenic:1

May 01, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1313_1314delAG alteration, located in exon 9 (coding exon 8) of the BRAT1 gene, consists of a deletion of 2 nucleotides from position 1313 to 1314, causing a translational frameshift with a predicted alternate stop codon after 51 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the c.1313_1314delAG (p.Q438Rfs*51) alteration has an overall frequency of 0.007% (15/228138) total alleles studied. The highest observed frequency was 0.013% (2/15466) of African alleles. This variant has been identified in the homozygous state and/or in conjunction with other BRAT1 variant(s) in individual(s) with features consistent with BRAT1-related neurodevelopmental disorder (Carapancea, 2023; Engel, 2023; Kim, 2022; Szymaska, 2018). Based on the available evidence, this alteration is classified as pathogenic. -

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

Pathogenic:1

May 10, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.32

Mutation Taster

=14/186

disease causing (ClinVar)

(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