rs776913277

Positions:

• chr7-2545044-G-GT

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_152743.4(BRAT1):​c.294_295insA​(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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:17
• Conservation: PhyloP100: 0.411

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]

ACMG classification

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/exons	MANE	Protein	UniProt
BRAT1	NM_152743.4	c.294_295insA	p.Leu99ThrfsTer92	frameshift_variant	4/14	ENST00000340611.9	NP_689956.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRAT1	ENST00000340611.9	c.294_295insA	p.Leu99ThrfsTer92	frameshift_variant	4/14	1	NM_152743.4	ENSP00000339637	P1
BRAT1	ENST00000467558.5	n.310_311insA		non_coding_transcript_exon_variant	3/10	5
BRAT1	ENST00000469750.5	n.518_519insA		non_coding_transcript_exon_variant	4/11	2
BRAT1	ENST00000421712.1	c.283-1083_283-1082insA		intron_variant, NMD_transcript_variant		3		ENSP00000409209

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152152 Hom.: 0 Cov.: 30

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: 34 AN: 141972 Hom.: 0 AF XY: 0.000236 AC XY: 18 AN XY: 76384

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.: 0 Cov.: 31 AF XY: 0.000325 AC XY: 215 AN XY: 662444

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: 32 AN: 152270 Hom.: 0 Cov.: 30 AF XY: 0.000107 AC XY: 8 AN XY: 74442

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.: 0

Bravo AF: 0.000193

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neonatal-onset encephalopathy with rigidity and seizures Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 14, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Apr 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 28, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Jul 10, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Mar 31, 2022	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 -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	Apr 20, 2018	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. -

not provided Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 15, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 05, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	BRAT1: PVS1, PM2, PM3 -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 19, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 31, 2023	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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Dec 28, 2016	- -

Neurodevelopmental disorder with cerebellar atrophy and with or without seizures Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 13, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 02, 2018	- -

BRAT1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 23, 2024

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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 23, 2020

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

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

Other links and lift over

dbSNP: rs776913277; hg19: chr7-2584678;