NM_152743.4:c.2389_2390delAA

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5

The NM_152743.4(BRAT1):c.2389_2390delAA(p.Lys797GlufsTer81) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

BRAT1
NM_152743.4 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 0.744

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

neonatal-onset encephalopathy with rigidity and seizures
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae)
neurodevelopmental disorder with cerebellar atrophy and with or without seizures
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics

BRAT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 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 0.0312 CDS is truncated, and there are 1 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-2538144-CTT-C is Pathogenic according to our data. Variant chr7-2538144-CTT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 861414.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAT1	NM_152743.4 link	c.2389_2390delAA	p.Lys797GlufsTer81	frameshift_variant	Exon 14 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.2389_2390delAA	p.Lys797GlufsTer81	frameshift_variant	Exon 14 of 14	1	NM_152743.4	ENSP00000339637.4	Q6PJG6-1
BRAT1	ENST00000467558.5 link	n.4175_4176delAA		non_coding_transcript_exon_variant	Exon 10 of 10	5
BRAT1	ENST00000469750.5 link	n.4961_4962delAA		non_coding_transcript_exon_variant	Exon 11 of 11	2
BRAT1	ENST00000493232.5 link	n.5095_5096delAA		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1456396

Hom.:

AF XY:

0.00

AC XY:

AN XY:

723580

African (AFR)

AF:

0.00

AC:

AN:

33404

American (AMR)

AF:

0.00

AC:

AN:

44600

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26084

East Asian (EAS)

AF:

0.00

AC:

AN:

39538

South Asian (SAS)

AF:

0.00

AC:

AN:

86088

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51988

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108842

Other (OTH)

AF:

0.00

AC:

AN:

60100

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Mar 30, 2023

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift variant predicted to result in protein truncation as the last 25 amino acids are replaced with 80 different amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD) -

Neonatal-onset encephalopathy with rigidity and seizures

Uncertain:1

Feb 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Lys797Glufs*81) in the BRAT1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 25 amino acid(s) of the BRAT1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRAT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 861414). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.74

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over