rs730880324

Positions:

• chr7-2543754-C-CT

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.638_639insA​(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:22 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/exons	MANE	UniProt
BRAT1	NM_152743.4	c.638_639insA	p.Val214GlyfsTer189	frameshift_variant	5/14	ENST00000340611.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRAT1	ENST00000340611.9	c.638_639insA	p.Val214GlyfsTer189	frameshift_variant	5/14	1	NM_152743.4	P1

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:22 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:9

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 17, 2022	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) -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 05, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 13, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	BRAT1: PP1:Strong, PVS1:Strong, PS3:Moderate -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 19, 2021	- -

Neonatal-onset encephalopathy with rigidity and seizures Pathogenic:7

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 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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2012	- -
Pathogenic, no assertion criteria provided	clinical testing	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	Jan 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	Apr 21, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Sep 02, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Jul 10, 2018	- -

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

Likely pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Oct 10, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	Sep 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 01, 2023	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2012	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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:1

Pathogenic, criteria provided, single submitter

clinical testing

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

-

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. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 25, 2017

- -

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;