rs776913277

Variant names:

• chr7-2545044-G-GT
• rs776913277
• NM_152743.4:c.294dupA

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_152743.4(BRAT1):​c.294dupA​(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:18
• Conservation: PhyloP100: 0.411
• Publications: 10 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 7-2545044-G-GT is Pathogenic according to our data. Variant chr7-2545044-G-GT is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 279703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152743.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAT1	NM_152743.4	MANE Select	c.294dupA	p.Leu99ThrfsTer92	frameshift	Exon 4 of 14	NP_689956.2
	BRAT1	NM_001350626.2		c.294dupA	p.Leu99ThrfsTer92	frameshift	Exon 4 of 14	NP_001337555.1
	BRAT1	NM_001350627.2		c.-95-1083dupA		intron	N/A	NP_001337556.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAT1	ENST00000340611.9	TSL:1 MANE Select	c.294dupA	p.Leu99ThrfsTer92	frameshift	Exon 4 of 14	ENSP00000339637.4
	BRAT1	ENST00000890463.1		c.294dupA	p.Leu99ThrfsTer92	frameshift	Exon 4 of 16	ENSP00000560522.1
	BRAT1	ENST00000917322.1		c.291dupA	p.Leu98ThrfsTer92	frameshift	Exon 4 of 16	ENSP00000587381.1

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

GnomAD2 exomes AF: 0.000239 AC: 34 AN: 141972 AF XY: 0.000236

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 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

African (AFR) AF: 0.0000335 AC: 1 AN: 29852

American (AMR) AF: 0.000180 AC: 5 AN: 27782

Ashkenazi Jewish (ASJ) AF: 0.000961 AC: 20 AN: 20812

East Asian (EAS) AF: 0.00 AC: 0 AN: 36198

South Asian (SAS) AF: 0.00 AC: 0 AN: 71928

European-Finnish (FIN) AF: 0.0000207 AC: 1 AN: 48236

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5378

European-Non Finnish (NFE) AF: 0.000379 AC: 401 AN: 1058126

Other (OTH) AF: 0.000359 AC: 20 AN: 55764

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152270 Hom.: 0 Cov.: 30 AF XY: 0.000107 AC XY: 8 AN XY: 74442

African (AFR) AF: 0.0000241 AC: 1 AN: 41562

American (AMR) AF: 0.000131 AC: 2 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000307 Hom.: 0

Bravo AF: 0.000193

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Neonatal-onset encephalopathy with rigidity and seizures (7)
6	-	-	not provided (6)
3	-	-	Neurodevelopmental disorder with cerebellar atrophy and with or without seizures (3)
1	-	-	BRAT1-related disorder (1)
1	-	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.41
Mutation Taster		=19/181	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs776913277; hg19: chr7-2584678;