rs140451075

Variant summary

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

The NM_152743.4(BRAT1):c.866G>C(p.Cys289Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00802 in 1,611,602 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0059 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0082 ( 71 hom. )

Consequence

BRAT1
NM_152743.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.99

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:

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=0.007962763).

BP6

Variant 7-2543261-C-G is Benign according to our data. Variant chr7-2543261-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 235265.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-2543261-C-G is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRAT1	NM_152743.4 linkuse as main transcript	c.866G>C	p.Cys289Ser	missense_variant	6/14	ENST00000340611.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRAT1	ENST00000340611.9 linkuse as main transcript	c.866G>C	p.Cys289Ser	missense_variant	6/14	1	NM_152743.4	P1	Q6PJG6-1

Frequencies

GnomAD3 genomes

AF:

0.00587

AC:

894

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00154

Gnomad AMI

AF:

0.0264

Gnomad AMR

AF:

0.00255

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00600

Gnomad FIN

AF:

0.00471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00983

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00585

AC:

1457

AN:

248892

Hom.:

AF XY:

0.00631

AC XY:

850

AN XY:

134714

show subpopulations

Gnomad AFR exome

AF:

0.00124

Gnomad AMR exome

AF:

0.00196

Gnomad ASJ exome

AF:

0.00221

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.00424

Gnomad FIN exome

AF:

0.00555

Gnomad NFE exome

AF:

0.00950

Gnomad OTH exome

AF:

0.00496

GnomAD4 exome

AF:

0.00825

AC:

12039

AN:

1459302

Hom.:

Cov.:

AF XY:

0.00820

AC XY:

5955

AN XY:

725846

show subpopulations

Gnomad4 AFR exome

AF:

0.00114

Gnomad4 AMR exome

AF:

0.00222

Gnomad4 ASJ exome

AF:

0.00253

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00451

Gnomad4 FIN exome

AF:

0.00582

Gnomad4 NFE exome

AF:

0.00967

Gnomad4 OTH exome

AF:

0.00639

GnomAD4 genome

AF:

0.00587

AC:

894

AN:

152300

Hom.:

Cov.:

AF XY:

0.00525

AC XY:

391

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00154

Gnomad4 AMR

AF:

0.00255

Gnomad4 ASJ

AF:

0.00259

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00580

Gnomad4 FIN

AF:

0.00471

Gnomad4 NFE

AF:

0.00985

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.00794

Hom.:

Bravo

AF:

0.00569

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00884

AC:

ExAC

AF:

0.00643

AC:

781

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 07, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 29, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	BRAT1: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 12, 2019	- -

Neonatal-onset encephalopathy with rigidity and seizures

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 21, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Neonatal-onset encephalopathy with rigidity and seizures;C4748032:Neurodevelopmental disorder with cerebellar atrophy and with or without seizures

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 02, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

Cadd

Benign

4.2

Dann

Benign

0.26

DEOGEN2

Benign

0.0011

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.092

LIST_S2

Benign

0.65

M_CAP

Benign

0.044

MetaRNN

Benign

0.0080

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.7

MutationTaster

Benign

1.0

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.33

REVEL

Benign

0.14

Sift

Benign

0.60

Sift4G

Benign

0.98

Polyphen

0.12

Vest4

0.23

MutPred

0.34

Gain of disorder (P = 9e-04);

MVP

0.43

MPC

0.059

ClinPred

0.00042

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.031

gMVP

0.11

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.

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