rs776913277

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_152743.4(BRAT1):c.294dupA(p.Leu99ThrfsTer92) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000319 in 1,506,346 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00033 ( 0 hom. )

Consequence

BRAT1
NM_152743.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17

Conservation

PhyloP100: 0.411

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 Pathogenic. Variant got 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 7-2545044-G-GT is Pathogenic according to our data. Variant chr7-2545044-G-GT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 279703.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.294dupA	p.Leu99ThrfsTer92	frameshift_variant	Exon 4 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.294dupA	p.Leu99ThrfsTer92	frameshift_variant	Exon 4 of 14	1	NM_152743.4	ENSP00000339637.4	Q6PJG6-1
BRAT1	ENST00000467558.5 link	n.310dupA		non_coding_transcript_exon_variant	Exon 3 of 10	5
BRAT1	ENST00000469750.5 link	n.518dupA		non_coding_transcript_exon_variant	Exon 4 of 11	2
BRAT1	ENST00000421712.1 link	n.283-1083dupA		intron_variant	Intron 2 of 4	3		ENSP00000409209.2	F8WDN5

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000239

AC:

AN:

141972

Hom.:

AF XY:

0.000236

AC XY:

AN XY:

76384

show subpopulations

Gnomad AFR exome

AF:

0.0000992

Gnomad AMR exome

AF:

0.000114

Gnomad ASJ exome

AF:

0.000801

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000407

Gnomad OTH exome

AF:

0.000297

GnomAD4 exome

AF:

0.000331

AC:

448

AN:

1354076

Hom.:

Cov.:

AF XY:

0.000325

AC XY:

215

AN XY:

662444

show subpopulations

Gnomad4 AFR exome

AF:

0.0000335

Gnomad4 AMR exome

AF:

0.000180

Gnomad4 ASJ exome

AF:

0.000961

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000207

Gnomad4 NFE exome

AF:

0.000379

Gnomad4 OTH exome

AF:

0.000359

GnomAD4 genome

AF:

0.000210

AC:

AN:

152270

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000307

Hom.:

Bravo

AF:

0.000193

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neonatal-onset encephalopathy with rigidity and seizures

Pathogenic:7

Apr 20, 2018

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This frameshifting variant is predicted to result in a premature stop codon and is therefore considered a loss-of-function mutation. This variant has been previously reported as a compound heterozygous change in individuals with neurodevelopmental phenotypes of variable severity (PMID: 26494257, 26483087). This variant is present as a heterozygous change in the gnomAD population database at a frequency of 0.023%. Based on the available evidence, the c.294dupA (p.Leu99ThrfsTer92) variant is classified as a pathogenic change. -

Apr 22, 2021

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 14, 2016

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 28, 2024

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Leu99ThrfsX92 variant in BRAT1 has been reported in the compound heterozygous state (confirmed in trans) in at least 5 individuals with clinical features of variable severity consistent with BRAT1-associated neurodevelopmental disorders and segregated with the phenotype in 2 affected relatives from 1 family (Hanes 2015 PMID: 26483087, Mundy 2016 PMID: 26494257, Oatts 2017 PMID: 28635423, Taylor 2019 PMID: 31345272, Stodberg 2020 PMID: 32964447). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 279703) and has been identified in 0.09% (22/24284) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org, v4.0.0), consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 99 and leads to a premature termination codon 92 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of function of the BRAT1 gene is an established disease mechanism in autosomal recessive BRAT1-related neurodevelopmental disorder. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive BRAT1-related neurodevelopmental disorders. ACMG/AMP Criteria applied: PVS1, PP1_Moderate, PM3. -

Mar 31, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with neurodevelopmental disorder with cerebellar atrophy and with or without seizures (MIM#618056) and lethal neonatal rigidity and multifocal seizure syndrome (MIM#614498). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (42 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic, and observed in individuals with neurodevelopmental disorder with cerebellar atrophy, with or without seizures, or lethal neonatal rigidity and multifocal seizure syndrome (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic and likely pathogenic, and observed in individuals with brain malformations (ClinVar, PMID: 32964447). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Jul 10, 2018

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 23, 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.Leu99Thrfs*92) 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 (rs776913277, gnomAD 0.08%). This premature translational stop signal has been observed in individual(s) with neonatal onset of hypertonia and seizures and progressive global developmental delay, visual impairment, microcephaly, hypertonia, hyperreflexia, and seizures (PMID: 26483087, 26494257). ClinVar contains an entry for this variant (Variation ID: 279703). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:6

May 31, 2023

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; This variant is associated with the following publications: (PMID: 27282546, 26494257, 27480663, 27282648, 31440721, 31980526, 28635423, 32964447, 26483087, 33726816, 35620305) -

May 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRAT1: PVS1, PM2, PM3 -

Jun 15, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 05, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 19, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 28, 2016

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neurodevelopmental disorder with cerebellar atrophy and with or without seizures

Pathogenic:2

Aug 02, 2018

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 13, 2021

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BRAT1-related disorder

Pathogenic:1

Mar 23, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRAT1 c.294dupA variant is predicted to result in a frameshift and premature protein termination (p.Leu99Thrfs*92). This variant has been reported in patients with BRAT1-associated neurodegenerative disorders (Hanes et al. 2015. PubMed ID: 26483087; Oatts et al. 2017. PubMed ID: 28635423). This variant is reported in 0.074% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. Frameshift variants in BRAT1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Nov 23, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.294dupA (p.L99Tfs*92) alteration, located in exon 4 (coding exon 3) of the BRAT1 gene, consists of a duplication of A at position 294, causing a translational frameshift with a predicted alternate stop codon after 92 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 the Genome Aggregation Database (gnomAD) database, the BRAT1 c.294dupA alteration was observed in 0.02% (42/173320) of total alleles studied, with a frequency of 0.07% (3/4034) in the Ashkenazi Jewish subpopulation. This alteration has been described with a second alteration in trans in multiple unrelated patients who present with developmental delay, microcephaly, abnormal muscle tone, and various other anomalies (Hanes, 2015; Mundy, 2015; Oatts, 2017, Taylor, 2019)._x000D_ _x000D_ Manual edits for references:_x000D_ _x000D_ Mundy SA, et al. (2015) Am. J. Med. Genet. A 170(3):699-702._x000D_ Oatts JT, et al. (2017) Ophthalmic Genet. 38(6):1-3. Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

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