rs2917726

Variant names:

• chr7-2538612-C-T
• rs2917726
• NM_152743.4:c.1923G>A

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.1923G>A​(p.Ala641Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0586 in 1,597,516 control chromosomes in the GnomAD database, including 4,204 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (349 hom., cov: 34)
  • Exomes 𝑓: 0.060 (3855 hom.)
• Consequence: BRAT1 NM_152743.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.460
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 7-2538612-C-T is Benign according to our data. Variant chr7-2538612-C-T is described in ClinVar as Benign. ClinVar VariationId is 585488.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.46 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.237 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.1923G>A	p.Ala641Ala	synonymous	Exon 14 of 14	NP_689956.2
	BRAT1	NM_001350626.2		c.2103G>A	p.Ala701Ala	synonymous	Exon 14 of 14	NP_001337555.1
	BRAT1	NM_001350627.2		c.1398G>A	p.Ala466Ala	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.1923G>A	p.Ala641Ala	synonymous	Exon 14 of 14	ENSP00000339637.4
	BRAT1	ENST00000890463.1		c.2160G>A	p.Ala720Ala	synonymous	Exon 16 of 16	ENSP00000560522.1
	BRAT1	ENST00000917322.1		c.2157G>A	p.Ala719Ala	synonymous	Exon 16 of 16	ENSP00000587381.1

Frequencies

GnomAD3 genomes AF: 0.0484 AC: 7365 AN: 152154 Hom.: 348 Cov.: 34

Gnomad AFR AF: 0.0125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0721

Gnomad ASJ AF: 0.0657

Gnomad EAS AF: 0.247

Gnomad SAS AF: 0.0624

Gnomad FIN AF: 0.0354

Gnomad MID AF: 0.0701

Gnomad NFE AF: 0.0505

Gnomad OTH AF: 0.0497

GnomAD2 exomes AF: 0.0680 AC: 15287 AN: 224900 AF XY: 0.0660

Gnomad AFR exome AF: 0.0104

Gnomad AMR exome AF: 0.0783

Gnomad ASJ exome AF: 0.0721

Gnomad EAS exome AF: 0.248

Gnomad FIN exome AF: 0.0307

Gnomad NFE exome AF: 0.0499

Gnomad OTH exome AF: 0.0546

GnomAD4 exome AF: 0.0596 AC: 86198 AN: 1445244 Hom.: 3855 Cov.: 83 AF XY: 0.0593 AC XY: 42657 AN XY: 719450

African (AFR) AF: 0.00936 AC: 313 AN: 33436

American (AMR) AF: 0.0782 AC: 3479 AN: 44508

Ashkenazi Jewish (ASJ) AF: 0.0726 AC: 1893 AN: 26058

East Asian (EAS) AF: 0.276 AC: 10919 AN: 39604

South Asian (SAS) AF: 0.0573 AC: 4929 AN: 86090

European-Finnish (FIN) AF: 0.0310 AC: 1203 AN: 38866

Middle Eastern (MID) AF: 0.0664 AC: 382 AN: 5756

European-Non Finnish (NFE) AF: 0.0533 AC: 59227 AN: 1110848

Other (OTH) AF: 0.0641 AC: 3853 AN: 60078

GnomAD4 genome AF: 0.0484 AC: 7374 AN: 152272 Hom.: 349 Cov.: 34 AF XY: 0.0510 AC XY: 3799 AN XY: 74456

African (AFR) AF: 0.0124 AC: 517 AN: 41570

American (AMR) AF: 0.0724 AC: 1108 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0657 AC: 228 AN: 3470

East Asian (EAS) AF: 0.248 AC: 1280 AN: 5160

South Asian (SAS) AF: 0.0626 AC: 302 AN: 4822

European-Finnish (FIN) AF: 0.0354 AC: 376 AN: 10622

Middle Eastern (MID) AF: 0.0753 AC: 22 AN: 292

European-Non Finnish (NFE) AF: 0.0505 AC: 3435 AN: 67998

Other (OTH) AF: 0.0501 AC: 106 AN: 2116

Alfa AF: 0.0500 Hom.: 44

Bravo AF: 0.0504

Asia WGS AF: 0.146 AC: 506 AN: 3478

EpiCase AF: 0.0508

EpiControl AF: 0.0489

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	5.0
DANN	Benign	0.68
PhyloP100		-0.46
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: rs2917726; hg19: chr7-2578246; COSMIC: COSV61394030; COSMIC: COSV61394030;