rs763527391

chr7-2538406-TCAAA-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_152743.4(BRAT1):c.2125_2128del(p.Phe709ThrfsTer17) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000502 in 1,613,342 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000052 (0 hom.)
• Consequence: BRAT1 NM_152743.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 5.85

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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.138 CDS is truncated, and there are 3 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-2538406-TCAAA-T is Pathogenic according to our data. Variant chr7-2538406-TCAAA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 372962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-2538406-TCAAA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRAT1	NM_152743.4	c.2125_2128del	p.Phe709ThrfsTer17	frameshift_variant	14/14	ENST00000340611.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRAT1	ENST00000340611.9	c.2125_2128del	p.Phe709ThrfsTer17	frameshift_variant	14/14	1	NM_152743.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152086 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000240 AC: 6 AN: 250228 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135596

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000520 AC: 76 AN: 1461256 Hom.: 0 AF XY: 0.0000495 AC XY: 36 AN XY: 726958

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000639

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152086 Hom.: 0 Cov.: 34 AF XY: 0.0000404 AC XY: 3 AN XY: 74294

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000227

EpiCase AF: 0.000273

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2016	The c.2125_2128delTTTG variant in the BRAT1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant causes a frameshift starting with codon Phenylalanine 709, changes this amino acid to a Threonine residue, and creates a premature Stop codon at position 17 of the new reading frame, denoted p.Phe709ThrfsX17. This variant is predicted to cause loss of normal protein function through protein truncation, as the last 113 amino acids of the protein are replaced by 16 incorrect amino acids. The c.2125_2128delTTTG variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.2125_2128delTTTG variant is a strong candidate for a pathogenic variant; however, the possibility it may be a rare benign variant cannot be excluded. -

BRAT1-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 25, 2023

The BRAT1 c.2125_2128delTTTG variant is predicted to result in a frameshift and premature protein termination (p.Phe709Thrfs*17). This variant has been reported in the compound heterozygous state in individuals with BRAT1-associated neurodegenerative disorder (Smith et al. 2016. PubMed ID: 27480663; Papuc et al. 2018. PubMed ID: 30552426). This variant is reported in 0.0044% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-2578040-TCAAA-T). Frameshift variants in BRAT1 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

Neonatal-onset encephalopathy with rigidity and seizures Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 10, 2024

This sequence change creates a premature translational stop signal (p.Phe709Thrfs*17) in the BRAT1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 113 amino acid(s) of the BRAT1 protein. This variant is present in population databases (rs763527391, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with BRAT1-related conditions (PMID: 27480663, 30552426). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372962). This variant disrupts a region of the BRAT1 protein in which other variant(s) (p.Ser747Thrfs*36) have been observed in individuals with BRAT1-related conditions (PMID: 28752061). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2017

- -

BRAT1-associated neurodegenerative disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Jan 07, 2020

This frameshifting variant in exon 14 of BRAT1 introduces a premature stop codon and is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported in the compound heterozygous state in patients with BRAT1-associated neurodegenerative disorder (PMID: 27480663, 30552426). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.002% (6/250228) and thus is presumed to be rare. Based on the available evidence, the c.2125_2128del (p.Phe709ThrfsTer17) variant is classified as Pathogenic. -

Neurodevelopmental disorder with cerebellar atrophy and with or without seizures Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 12, 2023

Variant summary: BRAT1 c.2125_2128delTTTG (p.Phe709ThrfsX17) results in a premature termination codon, predicted to cause a truncation in the last exon (exon 14) of the encoded protein affecting the last 113 amino acids, although nonsense mediated decay is not expected to occur. The variant allele was found at a frequency of 2.4e-05 in 250228 control chromosomes. c.2125_2128delTTTG has been reported in the literature in multiple compound heterozygous individuals affected with lethal neonatal rigidity and multifocal seizure syndrome, early-onset epileptic encephalopathy, or clinical features of Neurodevelopmental Disorder With Cerebellar Atrophy And With Or Without Seizures (e.g. Smith_2016, Papuc_2019, Qi_2022). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30552426, 35360849, 27480663). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=3) or likely pathogenic (n=3). Based on the evidence outlined above, the variant was 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: rs763527391; hg19: chr7-2578040;