7-2538295-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_152743.4(BRAT1):​c.2240C>T​(p.Ser747Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,460,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S747S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

BRAT1
NM_152743.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.396
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.16787788).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BRAT1NM_152743.4 linkuse as main transcriptc.2240C>T p.Ser747Phe missense_variant 14/14 ENST00000340611.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BRAT1ENST00000340611.9 linkuse as main transcriptc.2240C>T p.Ser747Phe missense_variant 14/141 NM_152743.4 P1Q6PJG6-1
BRAT1ENST00000467558.5 linkuse as main transcriptn.4026C>T non_coding_transcript_exon_variant 10/105
BRAT1ENST00000469750.5 linkuse as main transcriptn.4812C>T non_coding_transcript_exon_variant 11/112
BRAT1ENST00000493232.5 linkuse as main transcriptn.4946C>T non_coding_transcript_exon_variant 3/32

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
AF:
0.00000753
AC:
11
AN:
1460308
Hom.:
0
Cov.:
62
AF XY:
0.00000413
AC XY:
3
AN XY:
726502
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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:
0.00000810
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
34
Bravo
AF:
0.00000756

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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 28, 2021This sequence change replaces serine with phenylalanine at codon 747 of the BRAT1 protein (p.Ser747Phe). The serine residue is moderately conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with BRAT1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Benign
-0.50
CADD
Benign
15
DANN
Benign
0.90
DEOGEN2
Benign
0.013
T
Eigen
Benign
-0.56
Eigen_PC
Benign
-0.68
FATHMM_MKL
Benign
0.084
N
LIST_S2
Benign
0.78
T
M_CAP
Benign
0.023
T
MetaRNN
Benign
0.17
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.3
M
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.42
T
PROVEAN
Benign
-1.4
N
REVEL
Benign
0.024
Sift
Benign
0.049
D
Sift4G
Benign
0.16
T
Polyphen
0.72
P
Vest4
0.33
MutPred
0.20
Loss of glycosylation at S747 (P = 0.0074);
MVP
0.31
MPC
0.10
ClinPred
0.13
T
GERP RS
2.2
Varity_R
0.043
gMVP
0.31

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

LitVar

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

Other links and lift over

dbSNP: rs923807425; hg19: chr7-2577929; API