rs61746940

Variant names:

• chr7-2539290-G-A
• rs61746940
• NM_152743.4:c.1659C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-2539290-G-A
• chr7-2539290-G-T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_152743.4(BRAT1):​c.1659C>T​(p.Leu553Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00323 in 1,611,972 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0034 (15 hom.)
• Consequence: BRAT1 NM_152743.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.315
• Publications: 3 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 7-2539290-G-A is Benign according to our data. Variant chr7-2539290-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 472950.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.315 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 15 AR gene

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.1659C>T	p.Leu553Leu	synonymous	Exon 13 of 14	NP_689956.2	Q6PJG6-1
	BRAT1	NM_001350626.2		c.1659C>T	p.Leu553Leu	synonymous	Exon 13 of 14	NP_001337555.1
	BRAT1	NM_001350627.2		c.1134C>T	p.Leu378Leu	synonymous	Exon 12 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.1659C>T	p.Leu553Leu	synonymous	Exon 13 of 14	ENSP00000339637.4	Q6PJG6-1
	BRAT1	ENST00000890463.1		c.1896C>T	p.Leu632Leu	synonymous	Exon 15 of 16	ENSP00000560522.1
	BRAT1	ENST00000917322.1		c.1893C>T	p.Leu631Leu	synonymous	Exon 15 of 16	ENSP00000587381.1

Frequencies

GnomAD3 genomes AF: 0.00197 AC: 300 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000868

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00341

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00189 AC: 467 AN: 247306 AF XY: 0.00199

Gnomad AFR exome AF: 0.000632

Gnomad AMR exome AF: 0.000610

Gnomad ASJ exome AF: 0.00141

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000605

Gnomad NFE exome AF: 0.00317

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00337 AC: 4912 AN: 1459636 Hom.: 15 Cov.: 32 AF XY: 0.00333 AC XY: 2420 AN XY: 726072

African (AFR) AF: 0.000718 AC: 24 AN: 33448

American (AMR) AF: 0.000783 AC: 35 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 38 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00198 AC: 171 AN: 86186

European-Finnish (FIN) AF: 0.000842 AC: 44 AN: 52256

Middle Eastern (MID) AF: 0.000590 AC: 3 AN: 5084

European-Non Finnish (NFE) AF: 0.00400 AC: 4447 AN: 1111842

Other (OTH) AF: 0.00249 AC: 150 AN: 60294

GnomAD4 genome AF: 0.00197 AC: 300 AN: 152336 Hom.: 0 Cov.: 33 AF XY: 0.00165 AC XY: 123 AN XY: 74482

African (AFR) AF: 0.000866 AC: 36 AN: 41574

American (AMR) AF: 0.000980 AC: 15 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4832

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00341 AC: 232 AN: 68028

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00274 Hom.: 0

Bravo AF: 0.00202

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00436

EpiControl AF: 0.00284

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.2
DANN	Benign	0.52
PhyloP100		-0.32
Mutation Taster		=100/0	polymorphism

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: rs61746940; hg19: chr7-2578924;