chr7-2538057-C-G

Variant names:

• chr7-2538057-C-G
• rs1043294
• NM_152743.4:c.*12G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_152743.4(BRAT1):​c.*12G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,539,028 control chromosomes in the GnomAD database, including 20,015 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.12 (1520 hom., cov: 33)
  • Exomes 𝑓: 0.16 (18495 hom.)
• Consequence: BRAT1 NM_152743.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.53
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• neonatal-onset encephalopathy with rigidity and seizures

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• neurodevelopmental disorder with cerebellar atrophy and with or without seizures

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.164 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAT1	NM_152743.4	c.*12G>C		3_prime_UTR_variant	Exon 14 of 14	ENST00000340611.9	NP_689956.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAT1	ENST00000340611.9	c.*12G>C		3_prime_UTR_variant	Exon 14 of 14	1	NM_152743.4	ENSP00000339637.4
BRAT1	ENST00000467558.5	n.4264G>C		non_coding_transcript_exon_variant	Exon 10 of 10	5
BRAT1	ENST00000469750.5	n.5050G>C		non_coding_transcript_exon_variant	Exon 11 of 11	2
BRAT1	ENST00000493232.5	n.5184G>C		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18487 AN: 152104 Hom.: 1514 Cov.: 33

Gnomad AFR AF: 0.0312

Gnomad AMI AF: 0.0958

Gnomad AMR AF: 0.167

Gnomad ASJ AF: 0.0956

Gnomad EAS AF: 0.00271

Gnomad SAS AF: 0.0758

Gnomad FIN AF: 0.211

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.115

GnomAD2 exomes AF: 0.137 AC: 26844 AN: 195372 AF XY: 0.136

Gnomad AFR exome AF: 0.0259

Gnomad AMR exome AF: 0.189

Gnomad ASJ exome AF: 0.0925

Gnomad EAS exome AF: 0.00193

Gnomad FIN exome AF: 0.205

Gnomad NFE exome AF: 0.166

Gnomad OTH exome AF: 0.147

GnomAD4 exome AF: 0.157 AC: 217664 AN: 1386806 Hom.: 18495 Cov.: 31 AF XY: 0.154 AC XY: 105007 AN XY: 679802

African (AFR) AF: 0.0238 AC: 753 AN: 31580

American (AMR) AF: 0.188 AC: 6910 AN: 36710

Ashkenazi Jewish (ASJ) AF: 0.0924 AC: 2004 AN: 21682

East Asian (EAS) AF: 0.00121 AC: 47 AN: 38748

South Asian (SAS) AF: 0.0791 AC: 5956 AN: 75268

European-Finnish (FIN) AF: 0.207 AC: 10286 AN: 49722

Middle Eastern (MID) AF: 0.0621 AC: 333 AN: 5362

European-Non Finnish (NFE) AF: 0.171 AC: 183549 AN: 1070538

Other (OTH) AF: 0.137 AC: 7826 AN: 57196

GnomAD4 genome AF: 0.122 AC: 18501 AN: 152222 Hom.: 1520 Cov.: 33 AF XY: 0.121 AC XY: 9037 AN XY: 74396

African (AFR) AF: 0.0311 AC: 1293 AN: 41554

American (AMR) AF: 0.168 AC: 2572 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0956 AC: 332 AN: 3472

East Asian (EAS) AF: 0.00252 AC: 13 AN: 5162

South Asian (SAS) AF: 0.0746 AC: 360 AN: 4824

European-Finnish (FIN) AF: 0.211 AC: 2240 AN: 10594

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.167 AC: 11347 AN: 67992

Other (OTH) AF: 0.115 AC: 243 AN: 2116

Alfa AF: 0.135 Hom.: 349

Bravo AF: 0.115

Asia WGS AF: 0.0530 AC: 182 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 23% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 21. Only high quality variants are reported. -

not provided Benign:1

Jul 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.072
DANN	Benign	0.27
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1043294; hg19: chr7-2577691;