NM_152743.4:c.1594G>A

Variant names:

• chr7-2539547-C-T
• rs142129866
• NM_152743.4:c.1594G>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.1594G>A​(p.Gly532Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000507 in 1,559,722 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).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00053 (3 hom.)
• Consequence: BRAT1 NM_152743.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 1.72
• Publications: 2 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=0.065173596).
• BP6: Variant 7-2539547-C-T is Benign according to our data. Variant chr7-2539547-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 472947.
• 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.1594G>A	p.Gly532Arg	missense	Exon 12 of 14	NP_689956.2	Q6PJG6-1
	BRAT1	NM_001350626.2		c.1594G>A	p.Gly532Arg	missense	Exon 12 of 14	NP_001337555.1
	BRAT1	NM_001350627.2		c.1069G>A	p.Gly357Arg	missense	Exon 11 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.1594G>A	p.Gly532Arg	missense	Exon 12 of 14	ENSP00000339637.4	Q6PJG6-1
	BRAT1	ENST00000890463.1		c.1831G>A	p.Gly611Arg	missense	Exon 14 of 16	ENSP00000560522.1
	BRAT1	ENST00000917322.1		c.1828G>A	p.Gly610Arg	missense	Exon 14 of 16	ENSP00000587381.1

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000246 AC: 42 AN: 170600 AF XY: 0.000209

Gnomad AFR exome AF: 0.000302

Gnomad AMR exome AF: 0.0000375

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000623

Gnomad NFE exome AF: 0.000527

Gnomad OTH exome AF: 0.000215

GnomAD4 exome AF: 0.000533 AC: 750 AN: 1407514 Hom.: 3 Cov.: 32 AF XY: 0.000485 AC XY: 337 AN XY: 695402

African (AFR) AF: 0.000156 AC: 5 AN: 31998

American (AMR) AF: 0.0000266 AC: 1 AN: 37530

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25098

East Asian (EAS) AF: 0.00 AC: 0 AN: 36392

South Asian (SAS) AF: 0.00 AC: 0 AN: 80138

European-Finnish (FIN) AF: 0.0000202 AC: 1 AN: 49492

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5550

European-Non Finnish (NFE) AF: 0.000668 AC: 723 AN: 1083066

Other (OTH) AF: 0.000343 AC: 20 AN: 58250

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152208 Hom.: 0 Cov.: 33 AF XY: 0.000255 AC XY: 19 AN XY: 74364

African (AFR) AF: 0.0000965 AC: 4 AN: 41458

American (AMR) AF: 0.000131 AC: 2 AN: 15284

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000485 AC: 33 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000385 Hom.: 0

Bravo AF: 0.000310

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000702 AC: 6

ExAC AF: 0.000193 AC: 23

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0024	T
Eigen	Benign	-0.079
Eigen_PC	Benign	0.036
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.7
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.087
Sift	Benign	0.33	T
Sift4G	Benign	0.31	T
Polyphen		0.34	B
Vest4		0.20
MutPred		0.39		Gain of MoRF binding (P = 0.0168)
MVP		0.77
MPC		0.27
ClinPred		0.024	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.22
Mutation Taster		=98/2	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: rs142129866; hg19: chr7-2579181;