rs140833277

chr7-2543959-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1 BP4_Strong BP6

The NM_152743.4(BRAT1):c.434C>T(p.Ala145Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,566,410 control chromosomes in the GnomAD database, including 2 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A145A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00090 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: BRAT1 NM_152743.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 1.30

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_152743.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.020778626).
• BP6: Variant 7-2543959-G-A is Benign according to our data. Variant chr7-2543959-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 540180.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRAT1	NM_152743.4	c.434C>T	p.Ala145Val	missense_variant	5/14	ENST00000340611.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRAT1	ENST00000340611.9	c.434C>T	p.Ala145Val	missense_variant	5/14	1	NM_152743.4	P1

Frequencies

GnomAD3 genomes AF: 0.000902 AC: 136 AN: 150716 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00198

Gnomad ASJ AF: 0.00290

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000191

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.00290

GnomAD3 exomes AF: 0.000818 AC: 178 AN: 217476 Hom.: 0 AF XY: 0.000746 AC XY: 89 AN XY: 119224

Gnomad AFR exome AF: 0.000291

Gnomad AMR exome AF: 0.00108

Gnomad ASJ exome AF: 0.00214

Gnomad EAS exome AF: 0.0000604

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000863

Gnomad NFE exome AF: 0.00107

Gnomad OTH exome AF: 0.000196

GnomAD4 exome AF: 0.00114 AC: 1620 AN: 1415576 Hom.: 2 Cov.: 33 AF XY: 0.00109 AC XY: 762 AN XY: 697840

Gnomad4 AFR exome AF: 0.000247

Gnomad4 AMR exome AF: 0.000888

Gnomad4 ASJ exome AF: 0.00283

Gnomad4 EAS exome AF: 0.0000262

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000413

Gnomad4 NFE exome AF: 0.00131

Gnomad4 OTH exome AF: 0.00107

GnomAD4 genome AF: 0.000902 AC: 136 AN: 150834 Hom.: 0 Cov.: 31 AF XY: 0.00107 AC XY: 79 AN XY: 73722

Gnomad4 AFR AF: 0.000147

Gnomad4 AMR AF: 0.00198

Gnomad4 ASJ AF: 0.00290

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000191

Gnomad4 NFE AF: 0.00121

Gnomad4 OTH AF: 0.00287

Alfa AF: 0.00124 Hom.: 0

Bravo AF: 0.000922

ESP6500AA AF: 0.000230 AC: 1

ESP6500EA AF: 0.000947 AC: 8

ExAC AF: 0.000782 AC: 94

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 03, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2020	- -

BRAT1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 2022

This 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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	20
Dann	Benign	0.22
DEOGEN2	Benign	0.0023	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.028
Sift	Benign	0.25	T
Sift4G	Benign	0.80	T
Polyphen		0.033	B
Vest4		0.29
MVP		0.26
MPC		0.048
ClinPred		0.0061	T
GERP RS		3.3
Varity_R		0.023
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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

Other links and lift over

dbSNP: rs140833277; hg19: chr7-2583593; COSMIC: COSV100500406; COSMIC: COSV100500406;