rs60152725

Positions:

• chr7-2538326-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000340611.9(BRAT1):​c.2209C>T​(p.Arg737Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00435 in 1,613,002 control chromosomes in the GnomAD database, including 249 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R737Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.023 (121 hom., cov: 34)
  • Exomes 𝑓: 0.0024 (128 hom.)
• Consequence: BRAT1 ENST00000340611.9 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0380

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001966834).
• BP6: Variant 7-2538326-G-A is Benign according to our data. Variant chr7-2538326-G-A is described in ClinVar as [Benign]. Clinvar id is 446897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0758 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRAT1	NM_152743.4	c.2209C>T	p.Arg737Trp	missense_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.2209C>T	p.Arg737Trp	missense_variant	14/14	1	NM_152743.4	ENSP00000339637	P1
BRAT1	ENST00000467558.5	n.3995C>T		non_coding_transcript_exon_variant	10/10	5
BRAT1	ENST00000469750.5	n.4781C>T		non_coding_transcript_exon_variant	11/11	2
BRAT1	ENST00000493232.5	n.4915C>T		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.0230 AC: 3495 AN: 152196 Hom.: 122 Cov.: 34

Gnomad AFR AF: 0.0782

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0119

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.0205

GnomAD3 exomes AF: 0.00594 AC: 1475 AN: 248252 Hom.: 52 AF XY: 0.00438 AC XY: 591 AN XY: 134812

Gnomad AFR exome AF: 0.0772

Gnomad AMR exome AF: 0.00458

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000996

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000278

Gnomad OTH exome AF: 0.00361

GnomAD4 exome AF: 0.00241 AC: 3515 AN: 1460688 Hom.: 128 Cov.: 65 AF XY: 0.00211 AC XY: 1533 AN XY: 726670

Gnomad4 AFR exome AF: 0.0790

Gnomad4 AMR exome AF: 0.00490

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000453

Gnomad4 SAS exome AF: 0.000429

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000148

Gnomad4 OTH exome AF: 0.00681

GnomAD4 genome AF: 0.0230 AC: 3499 AN: 152314 Hom.: 121 Cov.: 34 AF XY: 0.0222 AC XY: 1652 AN XY: 74480

Gnomad4 AFR AF: 0.0780

Gnomad4 AMR AF: 0.0119

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.0203

Alfa AF: 0.00569 Hom.: 19

Bravo AF: 0.0262

ESP6500AA AF: 0.0765 AC: 337

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00736 AC: 893

Asia WGS AF: 0.00549 AC: 20 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 28, 2017

- -

Neonatal-onset encephalopathy with rigidity and seizures Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0022	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.033
Sift	Benign	0.039	D
Sift4G	Uncertain	0.028	D
Polyphen		0.0030	B
Vest4		0.12
MVP		0.22
MPC		0.047
ClinPred		0.015	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.027
gMVP		0.19

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: rs60152725; hg19: chr7-2577960;