chr7-2543590-C-A

Variant names:

• chr7-2543590-C-A
• rs1131691679
• NM_152743.4:c.803G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_152743.4(BRAT1):​c.803G>T​(p.Arg268Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000294 in 1,358,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R268C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: BRAT1 NM_152743.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.26
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-2543590-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 429928.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAT1	NM_152743.4	c.803G>T	p.Arg268Leu	missense_variant, splice_region_variant	Exon 5 of 14	ENST00000340611.9	NP_689956.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAT1	ENST00000340611.9	c.803G>T	p.Arg268Leu	missense_variant, splice_region_variant	Exon 5 of 14	1	NM_152743.4	ENSP00000339637.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000294 AC: 4 AN: 1358412 Hom.: 0 Cov.: 33 AF XY: 0.00000452 AC XY: 3 AN XY: 664026

African (AFR) AF: 0.00 AC: 0 AN: 30252

American (AMR) AF: 0.00 AC: 0 AN: 30154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19970

East Asian (EAS) AF: 0.00 AC: 0 AN: 38020

South Asian (SAS) AF: 0.0000428 AC: 3 AN: 70128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5276

European-Non Finnish (NFE) AF: 9.43e-7 AC: 1 AN: 1060124

Other (OTH) AF: 0.00 AC: 0 AN: 55902

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Dec 09, 2020

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.044	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.3
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.28
Sift	Uncertain	0.020	D
Sift4G	Uncertain	0.034	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.47		Gain of sheet (P = 0.0477);
MVP		0.66
MPC		0.34
ClinPred		0.96	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.60
Mutation Taster		=30/70	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.61		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.61		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1131691679; hg19: chr7-2583224;