dbSNP rs761588914: BRAT1:p.Glu817Gln (chr7-2538086-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_152743.4(BRAT1):c.2449G>C(p.Glu817Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000703 in 1,421,646 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. E817K) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

BRAT1
NM_152743.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.50

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0929884).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAT1	NM_152743.4 link	c.2449G>C	p.Glu817Gln	missense_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.2449G>C	p.Glu817Gln	missense_variant	Exon 14 of 14	1	NM_152743.4	ENSP00000339637.4	Q6PJG6-1
BRAT1	ENST00000467558.5 link	n.4235G>C		non_coding_transcript_exon_variant	Exon 10 of 10	5
BRAT1	ENST00000469750.5 link	n.5021G>C		non_coding_transcript_exon_variant	Exon 11 of 11	2
BRAT1	ENST00000493232.5 link	n.5155G>C		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.03e-7

AC:

AN:

1421646

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

701020

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32646

American (AMR)

AF:

0.00

AC:

AN:

42016

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24062

East Asian (EAS)

AF:

0.00

AC:

AN:

39026

South Asian (SAS)

AF:

0.00

AC:

AN:

82130

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51208

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5612

European-Non Finnish (NFE)

AF:

9.20e-7

AC:

AN:

1086370

Other (OTH)

AF:

0.00

AC:

AN:

58576

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.011

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.39

M_CAP

Benign

0.011

MetaRNN

Benign

0.093

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

PhyloP100

2.5

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.7

REVEL

Benign

0.024

Sift

Benign

0.10

Sift4G

Benign

0.24

Polyphen

0.062

Vest4

0.16

MutPred

0.24

Loss of solvent accessibility (P = 0.0509);

MVP

0.19

MPC

0.048

ClinPred

0.11

GERP RS

2.5

Varity_R

0.052

gMVP

0.30

Mutation Taster

=94/6

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

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rs761588914

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over