rs145833100

Variant names:

• chr7-2538494-C-T
• rs145833100
• NM_152743.4:c.2041G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_152743.4(BRAT1):​c.2041G>A​(p.Glu681Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00143 in 1,611,408 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E681A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00080 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0015 (3 hom.)
• Consequence: BRAT1 NM_152743.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:6
• Conservation: PhyloP100: -2.25
• Publications: 1 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047898293).
• BP6: Variant 7-2538494-C-T is Benign according to our data. Variant chr7-2538494-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 377362.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.2041G>A	p.Glu681Lys	missense	Exon 14 of 14	NP_689956.2	Q6PJG6-1
	BRAT1	NM_001350626.2		c.2221G>A	p.Glu741Lys	missense	Exon 14 of 14	NP_001337555.1
	BRAT1	NM_001350627.2		c.1516G>A	p.Glu506Lys	missense	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.2041G>A	p.Glu681Lys	missense	Exon 14 of 14	ENSP00000339637.4	Q6PJG6-1
	BRAT1	ENST00000890463.1		c.2278G>A	p.Glu760Lys	missense	Exon 16 of 16	ENSP00000560522.1
	BRAT1	ENST00000917322.1		c.2275G>A	p.Glu759Lys	missense	Exon 16 of 16	ENSP00000587381.1

Frequencies

GnomAD3 genomes AF: 0.000802 AC: 122 AN: 152208 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00135

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000791 AC: 195 AN: 246472 AF XY: 0.000812

Gnomad AFR exome AF: 0.000127

Gnomad AMR exome AF: 0.000841

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000950

Gnomad NFE exome AF: 0.00117

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.00150 AC: 2190 AN: 1459082 Hom.: 3 Cov.: 65 AF XY: 0.00146 AC XY: 1057 AN XY: 725950

African (AFR) AF: 0.000269 AC: 9 AN: 33472

American (AMR) AF: 0.000716 AC: 32 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86238

European-Finnish (FIN) AF: 0.000785 AC: 40 AN: 50936

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.00180 AC: 1998 AN: 1111804

Other (OTH) AF: 0.00147 AC: 89 AN: 60344

GnomAD4 genome AF: 0.000801 AC: 122 AN: 152326 Hom.: 0 Cov.: 34 AF XY: 0.000765 AC XY: 57 AN XY: 74498

African (AFR) AF: 0.000192 AC: 8 AN: 41580

American (AMR) AF: 0.000784 AC: 12 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000753 AC: 8 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00135 AC: 92 AN: 68010

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000938 Hom.: 0

Bravo AF: 0.000884

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.000758 AC: 92

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.00124

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	2	Neonatal-onset encephalopathy with rigidity and seizures (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	Intellectual disability (1)
-	-	1	Neonatal-onset encephalopathy with rigidity and seizures;C4748032:Neurodevelopmental disorder with cerebellar atrophy and with or without seizures (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.3
DANN	Benign	0.52
DEOGEN2	Benign	0.00066	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.36	N
PhyloP100		-2.2
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.0030
Sift	Benign	0.88	T
Sift4G	Benign	0.94	T
Polyphen		0.0010	B
Vest4		0.084
MVP		0.048
MPC		0.050
ClinPred		0.00041	T
GERP RS		-5.8
Varity_R		0.013
gMVP		0.24
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: rs145833100; hg19: chr7-2578128;