7-2538673-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The ENST00000340611.9(BRAT1):​c.1862G>A​(p.Arg621Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 1,598,336 control chromosomes in the GnomAD database, including 18 homozygotes. 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R621P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0019 ( 0 hom., cov: 34)
Exomes 𝑓: 0.0025 ( 18 hom. )

Consequence

BRAT1
ENST00000340611.9 missense

Scores

2
17

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.0450
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 Benign. Variant got -16 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.004225254).
BP6
Variant 7-2538673-C-T is Benign according to our data. Variant chr7-2538673-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 540188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High Homozygotes in GnomAdExome4 at 18 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
BRAT1NM_152743.4 linkuse as main transcriptc.1862G>A p.Arg621Gln missense_variant 14/14 ENST00000340611.9 NP_689956.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
BRAT1ENST00000340611.9 linkuse as main transcriptc.1862G>A p.Arg621Gln missense_variant 14/141 NM_152743.4 ENSP00000339637 P1Q6PJG6-1

Frequencies

GnomAD3 genomes
AF:
0.00185
AC:
282
AN:
152188
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.000458
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000981
Gnomad ASJ
AF:
0.00115
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00414
Gnomad FIN
AF:
0.00358
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00269
Gnomad OTH
AF:
0.000956
GnomAD3 exomes
AF:
0.00205
AC:
472
AN:
229856
Hom.:
5
AF XY:
0.00232
AC XY:
295
AN XY:
127172
show subpopulations
Gnomad AFR exome
AF:
0.000350
Gnomad AMR exome
AF:
0.000846
Gnomad ASJ exome
AF:
0.00133
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00528
Gnomad FIN exome
AF:
0.00254
Gnomad NFE exome
AF:
0.00207
Gnomad OTH exome
AF:
0.00257
GnomAD4 exome
AF:
0.00247
AC:
3573
AN:
1446030
Hom.:
18
Cov.:
70
AF XY:
0.00263
AC XY:
1894
AN XY:
719808
show subpopulations
Gnomad4 AFR exome
AF:
0.000239
Gnomad4 AMR exome
AF:
0.000760
Gnomad4 ASJ exome
AF:
0.000957
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.00561
Gnomad4 FIN exome
AF:
0.00253
Gnomad4 NFE exome
AF:
0.00252
Gnomad4 OTH exome
AF:
0.00186
GnomAD4 genome
AF:
0.00185
AC:
282
AN:
152306
Hom.:
0
Cov.:
34
AF XY:
0.00191
AC XY:
142
AN XY:
74478
show subpopulations
Gnomad4 AFR
AF:
0.000457
Gnomad4 AMR
AF:
0.000980
Gnomad4 ASJ
AF:
0.00115
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00414
Gnomad4 FIN
AF:
0.00358
Gnomad4 NFE
AF:
0.00269
Gnomad4 OTH
AF:
0.000946
Alfa
AF:
0.00188
Hom.:
0
Bravo
AF:
0.00149
TwinsUK
AF:
0.000809
AC:
3
ALSPAC
AF:
0.00337
AC:
13
ESP6500AA
AF:
0.000461
AC:
2
ESP6500EA
AF:
0.00201
AC:
17
ExAC
AF:
0.00207
AC:
248
Asia WGS
AF:
0.00173
AC:
6
AN:
3478
EpiCase
AF:
0.00191
EpiControl
AF:
0.00154

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Benign, criteria provided, single submitterclinical testingGeneDxSep 10, 2018- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenMar 01, 2024BRAT1: BP4, BS2 -
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsApr 05, 2019- -
BRAT1-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesNov 13, 2019This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Neonatal-onset encephalopathy with rigidity and seizures Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.091
BayesDel_addAF
Benign
-0.46
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
18
DANN
Uncertain
0.99
DEOGEN2
Benign
0.0058
T
Eigen
Benign
-0.37
Eigen_PC
Benign
-0.41
FATHMM_MKL
Benign
0.15
N
LIST_S2
Benign
0.78
T
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.0042
T
MetaSVM
Benign
-0.91
T
MutationAssessor
Benign
1.7
L
MutationTaster
Benign
0.96
N
PrimateAI
Benign
0.27
T
PROVEAN
Benign
-1.0
N
REVEL
Benign
0.076
Sift
Benign
0.20
T
Sift4G
Benign
0.14
T
Polyphen
0.74
P
Vest4
0.12
MVP
0.57
MPC
0.064
ClinPred
0.0066
T
GERP RS
3.4
Varity_R
0.077
gMVP
0.18

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs138077616; hg19: chr7-2578307; API