Variant 7-2539852-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_152743.4(BRAT1):c.1432C>G(p.Leu478Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000967 in 1,447,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000097 ( 0 hom. )

Consequence

BRAT1
NM_152743.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.38

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRAT1	NM_152743.4 linkuse as main transcript	c.1432C>G	p.Leu478Val	missense_variant	11/14	ENST00000340611.9	NP_689956.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRAT1	ENST00000340611.9 linkuse as main transcript	c.1432C>G	p.Leu478Val	missense_variant	11/14	1	NM_152743.4	ENSP00000339637	P1	Q6PJG6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000890

AC:

AN:

224844

Hom.:

AF XY:

0.00

AC XY:

AN XY:

122422

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000982

Gnomad OTH exome

AF:

0.000184

GnomAD4 exome

AF:

0.00000967

AC:

AN:

1447628

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

719518

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000127

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000573

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Neonatal-onset encephalopathy with rigidity and seizures

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 19, 2019

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with BRAT1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with valine at codon 478 of the BRAT1 protein (p.Leu478Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.088

BayesDel_noAF

Benign

-0.36

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0060

Eigen

Benign

0.16

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.78

M_CAP

Benign

0.039

MetaRNN

Benign

0.27

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.2

MutationTaster

Benign

0.99

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.4

REVEL

Benign

0.083

Sift

Uncertain

0.014

Sift4G

Benign

0.085

Polyphen

0.88

Vest4

0.48

MutPred

0.26

Gain of MoRF binding (P = 0.082);

MVP

0.30

MPC

0.12

ClinPred

0.40

GERP RS

4.3

Varity_R

0.13

gMVP

0.27

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.73

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.73

Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over