rs730880324

Variant names:

• chr7-2543754-C-CT
• rs730880324
• NM_152743.4:c.638dupA

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.638dupA​(p.Val214GlyfsTer189) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000258 in 1,605,932 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 0.00020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: BRAT1 NM_152743.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:24 O:1
• Conservation: PhyloP100: 0.315

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 7-2543754-C-CT is Pathogenic according to our data. Variant chr7-2543754-C-CT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 31199.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	c.638dupA	p.Val214GlyfsTer189	frameshift_variant	Exon 5 of 14	ENST00000340611.9	NP_689956.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAT1	ENST00000340611.9	c.638dupA	p.Val214GlyfsTer189	frameshift_variant	Exon 5 of 14	1	NM_152743.4	ENSP00000339637.4

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152208 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000246 AC: 61 AN: 248110 Hom.: 0 AF XY: 0.000231 AC XY: 31 AN XY: 134418

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000204

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.000465

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000264 AC: 384 AN: 1453724 Hom.: 0 Cov.: 33 AF XY: 0.000254 AC XY: 183 AN XY: 721862

Gnomad4 AFR exome AF: 0.0000600

Gnomad4 AMR exome AF: 0.000248

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000381

Gnomad4 NFE exome AF: 0.000316

Gnomad4 OTH exome AF: 0.000267

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152208 Hom.: 0 Cov.: 31 AF XY: 0.000148 AC XY: 11 AN XY: 74342

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0178 Hom.: 822

Bravo AF: 0.000298

EpiCase AF: 0.000491

EpiControl AF: 0.000475

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:24 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:9

Dec 05, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRAT1: PVS1, PM3:Strong, PP1:Strong, PM2, PS3:Moderate -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 17, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate aggregation of mutant BRAT1 protein in the cytoplasm suggesting protein destabilization (Puffenberger et al., 2012); 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: 25356970, 22279524, 26494257, 25319849, 27282546, 26535877, 26947546, 29997391, 30552426, 31028937, 27282648, 31589614, 31980526, 34426522, 25500575) -

Apr 19, 2021

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 13, 2017

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Neonatal-onset encephalopathy with rigidity and seizures Pathogenic:8

Apr 21, 2022

Centogene AG - the Rare Disease Company

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Sep 02, 2021

DASA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.638dup;p.(Val214Glyfs*189) is a null frameshift variant in the BRAT1 gene with an insertion of 1 base pair - PVS1; well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 22279524) - PS3; this variant has been reported as homozygous or compound heterozygous in several individuals with lethal neonatal rigidity and seizure syndrome (PMID: 27282648; 27282546; 22279524; 26535877; 26535877; 26947546 and GeneOne, DASA), and ClinVar contains an entry for this variant (Clinvar ID: 31199) - PS4; this variant is present in population databases (rs730880324, gnomAD frequency 0.02%; ABraOM frequency 0.04% - http://abraom.ib.usp.br/); variant detected in trans with a pathogenic variant (PMID: 27282648; 27282546; 22279524; 26535877; 26535877; 26947546) - PM3_strong; this variant has been observed to segregate in families (PMID: 27282648; 27282546; 26535877; 26947546) - PP1_strong. For these reasons, this variant was classified as pathogenic. -

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 detected as a homozygous change in individuals with lethal neonatal rigidity and seizure syndrome (PMID: 22279524). It has also been reported in the compound heterozygous state in individuals with milder phenotypes (PMID: 27282648, 27282546). This variant is present as a heterozygous change in the gnomAD population database at a frequency of 0.024%. Based on the available evidence, the c.638dupA (p.Val214GlyfsTer189) variant is classified as pathogenic. -

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 22, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2025

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.Val214Glyfs*189) 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 (rs730880324, gnomAD 0.05%). This premature translational stop signal has been observed in individuals with lethal neonatal rigidity and seizure syndrome and/or progressive encephalopathy, early-onset epileptic encephalopathy, ataxia, and developmental delay (PMID: 22279524, 26535877, 26947546, 27282546, 27282648). This variant is also known as c.638_639insA. ClinVar contains an entry for this variant (Variation ID: 31199). For these reasons, this variant has been classified as Pathogenic. -

Jul 10, 2018

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neurodevelopmental disorder with cerebellar atrophy and with or without seizures Pathogenic:4 Other:1

Jun 01, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: C7orf27 (BRAT1) c.638dupA (p.Val214GlyfsX189) 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 0.00024 in 279484 control chromosomes (gnomAD). c.638dupA has been reported in the literature as a biallelic genotype in individuals affected with lethal neonatal rigidity and seizure syndrome, neurodevelopmental disorder with cerebellar atrophy, and in individuals with nonprogressive congenital ataxia and shrunken cerebellum (e.g. Puffenberger_2012, Nuovo_2022). These data indicate that the variant is very likely to be associated with disease. Additionally, overexpression of the variant protein in vitro resulted in abolished nuclear localization and demonstrated protein instability (e.g. Puffenberger_2012). The following publications have been ascertained in the context of this evaluation (PMID: 34747546, 22279524). Fourteen submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=13)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Sep 22, 2022

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 10, 2019

New York Genome Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpretted as Pathogenic and reported on 05-31-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

BRAT1-related disorder Pathogenic:2

-

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 in exon 5 of 14 introduces a premature stop codon and is therefore 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 as a homozygous change in multiple individuals with Lethal Neonatal Rigidity & Seizure Syndrome (PMID: 22279524, 26535877, 26947546, 27282648, 27282546). It has also been reported in the compound heterozygous state in individuals with milder phenotypes (PMID: 27282648, 27282546). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.024% (66/279484) and thus is presumed to be rare. Based on the available evidence, the c.638dup (p.Val214GlyfsTer189) variant is classified as Pathogenic. -

Jun 01, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRAT1 c.638dupA variant is predicted to result in a frameshift and premature protein termination (p.Val214Glyfs*189). This variant has been reported in the homozygous state to be causative for lethal neonatal rigidity & seizure syndrome (Puffenberger et al. 2012. PubMed ID: 22279524, reported as c.638_639insA; Srivastava et al. 2016. PubMed ID: 27282546). This variant has also been reported in individuals with progressive recessive encephalopathy (Fernández-Jaén et al. 2016. PubMed ID: 26947546; Valence et al. 2018. PubMed ID: 29997391). We classify this variant as pathogenic. -

Inborn genetic diseases Pathogenic:1

Jan 25, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs730880324; hg19: chr7-2583388;