rs140451075

Variant names:

• chr7-2543261-C-G
• rs140451075
• NM_152743.4:c.866G>C

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.866G>C​(p.Cys289Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00802 in 1,611,602 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 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 0.0059 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0082 (71 hom.)
• Consequence: BRAT1 NM_152743.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: -1.99
• Publications: 3 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007962763).
• BP6: Variant 7-2543261-C-G is Benign according to our data. Variant chr7-2543261-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235265.
• BS2: High Homozygotes in GnomAd4 at 4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAT1	NM_152743.4	MANE Select	c.866G>C	p.Cys289Ser	missense	Exon 6 of 14	NP_689956.2
	BRAT1	NM_001350626.2		c.866G>C	p.Cys289Ser	missense	Exon 6 of 14	NP_001337555.1
	BRAT1	NM_001350627.2		c.341G>C	p.Cys114Ser	missense	Exon 5 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.866G>C	p.Cys289Ser	missense	Exon 6 of 14	ENSP00000339637.4
	BRAT1	ENST00000421712.1	TSL:3	n.*211G>C		non_coding_transcript_exon	Exon 4 of 5	ENSP00000409209.2
	BRAT1	ENST00000467558.5	TSL:5	n.1148G>C		non_coding_transcript_exon	Exon 4 of 10

Frequencies

GnomAD3 genomes AF: 0.00587 AC: 894 AN: 152182 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.0264

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00600

Gnomad FIN AF: 0.00471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00983

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00585 AC: 1457 AN: 248892 AF XY: 0.00631

Gnomad AFR exome AF: 0.00124

Gnomad AMR exome AF: 0.00196

Gnomad ASJ exome AF: 0.00221

Gnomad EAS exome AF: 0.000111

Gnomad FIN exome AF: 0.00555

Gnomad NFE exome AF: 0.00950

Gnomad OTH exome AF: 0.00496

GnomAD4 exome AF: 0.00825 AC: 12039 AN: 1459302 Hom.: 71 Cov.: 31 AF XY: 0.00820 AC XY: 5955 AN XY: 725846

African (AFR) AF: 0.00114 AC: 38 AN: 33396

American (AMR) AF: 0.00222 AC: 99 AN: 44518

Ashkenazi Jewish (ASJ) AF: 0.00253 AC: 66 AN: 26068

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39518

South Asian (SAS) AF: 0.00451 AC: 388 AN: 86090

European-Finnish (FIN) AF: 0.00582 AC: 307 AN: 52710

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5754

European-Non Finnish (NFE) AF: 0.00967 AC: 10744 AN: 1110984

Other (OTH) AF: 0.00639 AC: 385 AN: 60264

GnomAD4 genome AF: 0.00587 AC: 894 AN: 152300 Hom.: 4 Cov.: 32 AF XY: 0.00525 AC XY: 391 AN XY: 74460

African (AFR) AF: 0.00154 AC: 64 AN: 41570

American (AMR) AF: 0.00255 AC: 39 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00580 AC: 28 AN: 4826

European-Finnish (FIN) AF: 0.00471 AC: 50 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00985 AC: 670 AN: 68018

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00794 Hom.: 2

Bravo AF: 0.00569

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00884 AC: 76

ExAC AF: 0.00643 AC: 781

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Inborn genetic diseases (1)
-	1	-	Intellectual disability (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)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	4.2
DANN	Benign	0.26
DEOGEN2	Benign	0.0011	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.7	L
PhyloP100		-2.0
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.14
Sift	Benign	0.60	T
Sift4G	Benign	0.98	T
Polyphen		0.12	B
Vest4		0.23
MutPred		0.34		Gain of disorder (P = 9e-04)
MVP		0.43
MPC		0.059
ClinPred		0.00042	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.031
gMVP		0.11
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: rs140451075; hg19: chr7-2582895;