chr7-2538673-C-T

Position:

• chr7-2538673-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_152743.4(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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0025 (18 hom.)
• Consequence: BRAT1 NM_152743.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0450

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 (HGNC:):

ACMG classification

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
BRAT1	NM_152743.4	c.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
BRAT1	ENST00000340611.9	c.1862G>A	p.Arg621Gln	missense_variant	14/14	1	NM_152743.4	ENSP00000339637.4

Frequencies

GnomAD3 genomes AF: 0.00185 AC: 282 AN: 152188 Hom.: 0 Cov.: 34

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

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

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

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

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 10, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	BRAT1: BP4, BS2 -

BRAT1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 13, 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). -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 16, 2024

- -

Neonatal-onset encephalopathy with rigidity and seizures Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 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
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

Other links and lift over

dbSNP: rs138077616; hg19: chr7-2578307;