7-2538603-T-C

Variant names:

• chr7-2538603-T-C
• rs4719552
• NM_152743.4:c.1932A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_152743.4(BRAT1):​c.1932A>G​(p.Arg644Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.362 in 1,597,032 control chromosomes in the GnomAD database, including 109,578 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R644R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.45 (16930 hom., cov: 33)
  • Exomes 𝑓: 0.35 (92648 hom.)
• Consequence: BRAT1 NM_152743.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.00800
• Publications: 13 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, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 7-2538603-T-C is Benign according to our data. Variant chr7-2538603-T-C is described in ClinVar as Benign. ClinVar VariationId is 585489.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.008 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.662 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152743.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAT1	NM_152743.4	MANE Select	c.1932A>G	p.Arg644Arg	synonymous	Exon 14 of 14	NP_689956.2	Q6PJG6-1
	BRAT1	NM_001350626.2		c.2112A>G	p.Arg704Arg	synonymous	Exon 14 of 14	NP_001337555.1
	BRAT1	NM_001350627.2		c.1407A>G	p.Arg469Arg	synonymous	Exon 13 of 13	NP_001337556.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAT1	ENST00000340611.9	TSL:1 MANE Select	c.1932A>G	p.Arg644Arg	synonymous	Exon 14 of 14	ENSP00000339637.4	Q6PJG6-1
	BRAT1	ENST00000890463.1		c.2169A>G	p.Arg723Arg	synonymous	Exon 16 of 16	ENSP00000560522.1
	BRAT1	ENST00000917322.1		c.2166A>G	p.Arg722Arg	synonymous	Exon 16 of 16	ENSP00000587381.1

Frequencies

GnomAD3 genomes AF: 0.448 AC: 68051 AN: 151896 Hom.: 16898 Cov.: 33

Gnomad AFR AF: 0.668

Gnomad AMI AF: 0.462

Gnomad AMR AF: 0.418

Gnomad ASJ AF: 0.286

Gnomad EAS AF: 0.369

Gnomad SAS AF: 0.337

Gnomad FIN AF: 0.489

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.338

Gnomad OTH AF: 0.421

GnomAD2 exomes AF: 0.385 AC: 86750 AN: 225130 AF XY: 0.376

Gnomad AFR exome AF: 0.678

Gnomad AMR exome AF: 0.430

Gnomad ASJ exome AF: 0.299

Gnomad EAS exome AF: 0.362

Gnomad FIN exome AF: 0.492

Gnomad NFE exome AF: 0.348

Gnomad OTH exome AF: 0.370

GnomAD4 exome AF: 0.353 AC: 509491 AN: 1445018 Hom.: 92648 Cov.: 63 AF XY: 0.350 AC XY: 252045 AN XY: 719226

African (AFR) AF: 0.677 AC: 22632 AN: 33426

American (AMR) AF: 0.430 AC: 19038 AN: 44310

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 7753 AN: 26046

East Asian (EAS) AF: 0.363 AC: 14389 AN: 39586

South Asian (SAS) AF: 0.331 AC: 28452 AN: 86054

European-Finnish (FIN) AF: 0.477 AC: 18792 AN: 39374

Middle Eastern (MID) AF: 0.360 AC: 2074 AN: 5762

European-Non Finnish (NFE) AF: 0.337 AC: 374456 AN: 1110390

Other (OTH) AF: 0.365 AC: 21905 AN: 60070

GnomAD4 genome AF: 0.448 AC: 68137 AN: 152014 Hom.: 16930 Cov.: 33 AF XY: 0.450 AC XY: 33438 AN XY: 74316

African (AFR) AF: 0.668 AC: 27731 AN: 41504

American (AMR) AF: 0.419 AC: 6402 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.286 AC: 993 AN: 3470

East Asian (EAS) AF: 0.368 AC: 1887 AN: 5130

South Asian (SAS) AF: 0.335 AC: 1619 AN: 4826

European-Finnish (FIN) AF: 0.489 AC: 5169 AN: 10570

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.338 AC: 22932 AN: 67920

Other (OTH) AF: 0.419 AC: 885 AN: 2112

Alfa AF: 0.286 Hom.: 1169

Bravo AF: 0.454

Asia WGS AF: 0.352 AC: 1221 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Neonatal-onset encephalopathy with rigidity and seizures (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.2
DANN	Benign	0.42
PhyloP100		0.0080
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: rs4719552; hg19: chr7-2578237; COSMIC: COSV61394696; COSMIC: COSV61394696;