Genetic Variant BRAT1:c.1134+8C>A (chr7-2541710-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_152743.4(BRAT1):c.1134+8C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,450,566 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

BRAT1
NM_152743.4 splice_region, intron

Scores

Splicing: ADA: 0.001427

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.873

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, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P
neurodevelopmental disorder with cerebellar atrophy and with or without seizures
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics

BRAT1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
BRAT1	NM_152743.4	MANE Select	c.1134+8C>A	splice_region intron	N/A	NP_689956.2	Q6PJG6-1
BRAT1	NM_001350626.2		c.1134+8C>A	splice_region intron	N/A	NP_001337555.1
BRAT1	NM_001350627.2		c.609+8C>A	splice_region intron	N/A	NP_001337556.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
BRAT1	ENST00000340611.9	TSL:1 MANE Select	c.1134+8C>A	splice_region intron	N/A	ENSP00000339637.4	Q6PJG6-1
BRAT1	ENST00000890463.1		c.1134+8C>A	splice_region intron	N/A	ENSP00000560522.1
BRAT1	ENST00000917322.1		c.1131+8C>A	splice_region intron	N/A	ENSP00000587381.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1450566

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721064

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33358

American (AMR)

AF:

0.00

AC:

AN:

43210

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25804

East Asian (EAS)

AF:

0.00

AC:

AN:

39344

South Asian (SAS)

AF:

0.00

AC:

AN:

84946

European-Finnish (FIN)

AF:

0.0000199

AC:

AN:

50164

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5610

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108224

Other (OTH)

AF:

0.00

AC:

AN:

59906

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

3.8

(source)

DANN

Benign

0.59

PhyloP100

-0.87

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0014

dbscSNV1_RF

Benign

0.044

SpliceAI score (max)

0.50

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.50

Position offset: 4

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over