rs199766692

Variant names:

• chr7-2539248-G-A
• rs199766692
• NM_152743.4:c.1701C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_152743.4(BRAT1):​c.1701C>T​(p.Thr567Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00014 in 1,611,448 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: BRAT1 NM_152743.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.90
• Publications: 0 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 -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 7-2539248-G-A is Benign according to our data. Variant chr7-2539248-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 540178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.9 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAT1	NM_152743.4	MANE Select	c.1701C>T	p.Thr567Thr	synonymous	Exon 13 of 14	NP_689956.2
	BRAT1	NM_001350626.2		c.1701C>T	p.Thr567Thr	synonymous	Exon 13 of 14	NP_001337555.1
	BRAT1	NM_001350627.2		c.1176C>T	p.Thr392Thr	synonymous	Exon 12 of 13	NP_001337556.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAT1	ENST00000340611.9	TSL:1 MANE Select	c.1701C>T	p.Thr567Thr	synonymous	Exon 13 of 14	ENSP00000339637.4
	BRAT1	ENST00000467558.5	TSL:5	n.3073C>T		non_coding_transcript_exon	Exon 10 of 10
	BRAT1	ENST00000469750.5	TSL:2	n.4273C>T		non_coding_transcript_exon	Exon 10 of 11

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152220 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000285 AC: 70 AN: 245876 AF XY: 0.000314

Gnomad AFR exome AF: 0.000127

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00486

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000100

Gnomad OTH exome AF: 0.000499

GnomAD4 exome AF: 0.000136 AC: 199 AN: 1459110 Hom.: 0 Cov.: 32 AF XY: 0.000153 AC XY: 111 AN XY: 725860

African (AFR) AF: 0.0000598 AC: 2 AN: 33430

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00532 AC: 139 AN: 26118

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

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52148

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4682

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1111902

Other (OTH) AF: 0.000315 AC: 19 AN: 60236

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152338 Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7 AN XY: 74488

African (AFR) AF: 0.0000241 AC: 1 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000559 Hom.: 0

Bravo AF: 0.000174

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.19
DANN	Benign	0.40
PhyloP100		-2.9

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: rs199766692; hg19: chr7-2578882;