rs61753093

Positions:

• chr7-2538327-C-A
• chr7-2538327-C-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The ENST00000340611.9(BRAT1):​c.2208G>T​(p.Leu736=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00255 in 1,613,090 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L736L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0026 (13 hom.)
• Consequence: BRAT1 ENST00000340611.9 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.431

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 Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 7-2538327-C-A is Benign according to our data. Variant chr7-2538327-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 472963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.431 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRAT1	NM_152743.4	c.2208G>T	p.Leu736=	synonymous_variant	14/14	ENST00000340611.9	NP_689956.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRAT1	ENST00000340611.9	c.2208G>T	p.Leu736=	synonymous_variant	14/14	1	NM_152743.4	ENSP00000339637	P1
BRAT1	ENST00000467558.5	n.3994G>T		non_coding_transcript_exon_variant	10/10	5
BRAT1	ENST00000469750.5	n.4780G>T		non_coding_transcript_exon_variant	11/11	2
BRAT1	ENST00000493232.5	n.4914G>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.00184 AC: 280 AN: 152216 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00930

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00245

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00259 AC: 644 AN: 248466 Hom.: 3 AF XY: 0.00287 AC XY: 387 AN XY: 134886

Gnomad AFR exome AF: 0.000312

Gnomad AMR exome AF: 0.00148

Gnomad ASJ exome AF: 0.00569

Gnomad EAS exome AF: 0.0000553

Gnomad SAS exome AF: 0.00644

Gnomad FIN exome AF: 0.000372

Gnomad NFE exome AF: 0.00281

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00262 AC: 3826 AN: 1460756 Hom.: 13 Cov.: 66 AF XY: 0.00273 AC XY: 1986 AN XY: 726700

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.00528

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00652

Gnomad4 FIN exome AF: 0.000286

Gnomad4 NFE exome AF: 0.00257

Gnomad4 OTH exome AF: 0.00263

GnomAD4 genome AF: 0.00184 AC: 281 AN: 152334 Hom.: 1 Cov.: 34 AF XY: 0.00203 AC XY: 151 AN XY: 74506

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00952

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00246

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00238 Hom.: 0

Bravo AF: 0.00163

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00273

EpiControl AF: 0.00373

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	BRAT1: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 07, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 08, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

BRAT1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 24, 2019

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.18
DANN	Benign	0.51

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

Other links and lift over

dbSNP: rs61753093; hg19: chr7-2577961;