Genetic Variant BRAT1:p.Gly576Asp (chr7-2539222-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_152743.4(BRAT1):c.1727G>A(p.Gly576Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,274 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G576A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

BRAT1
NM_152743.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.03

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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	HGVSp	Effect	Exon Rank	Protein
BRAT1	NM_152743.4	MANE Select	c.1727G>A	p.Gly576Asp	missense	Exon 13 of 14	NP_689956.2
BRAT1	NM_001350626.2		c.1727G>A	p.Gly576Asp	missense	Exon 13 of 14	NP_001337555.1
BRAT1	NM_001350627.2		c.1202G>A	p.Gly401Asp	missense	Exon 12 of 13	NP_001337556.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BRAT1	ENST00000340611.9	TSL:1 MANE Select	c.1727G>A	p.Gly576Asp	missense	Exon 13 of 14	ENSP00000339637.4
BRAT1	ENST00000467558.5	TSL:5	n.3099G>A		non_coding_transcript_exon	Exon 10 of 10
BRAT1	ENST00000469750.5	TSL:2	n.4299G>A		non_coding_transcript_exon	Exon 10 of 11

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458274

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725358

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33414

American (AMR)

AF:

0.00

AC:

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26104

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86142

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52092

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4416

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111558

Other (OTH)

AF:

0.00

AC:

AN:

60178

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.097

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0028

Eigen

Benign

0.00034

Eigen_PC

Benign

-0.081

FATHMM_MKL

Benign

0.38

LIST_S2

Benign

0.78

M_CAP

Benign

0.024

MetaRNN

Uncertain

0.54

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

PhyloP100

2.0

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.6

REVEL

Benign

0.13

Sift

Benign

0.094

Sift4G

Benign

0.55

Polyphen

1.0

Vest4

0.62

MutPred

0.17

Loss of helix (P = 0.028)

MVP

0.41

MPC

0.33

ClinPred

0.76

GERP RS

4.9

Varity_R

0.10

gMVP

0.23

Mutation Taster

=95/5

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over