rs140833277

Variant names:

• chr7-2543959-G-A
• rs140833277
• NM_152743.4:c.434C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-2543959-G-A
• chr7-2543959-G-C
• chr7-2543959-G-T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS2

The NM_152743.4(BRAT1):​c.434C>T​(p.Ala145Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,566,410 control chromosomes in the GnomAD database, including 2 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A145T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00090 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: BRAT1 NM_152743.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 1.30
• Publications: 5 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 -7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 10 uncertain in NM_152743.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.020778626).
• BP6: Variant 7-2543959-G-A is Benign according to our data. Variant chr7-2543959-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 540180.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.434C>T	p.Ala145Val	missense	Exon 5 of 14	NP_689956.2	Q6PJG6-1
	BRAT1	NM_001350626.2		c.434C>T	p.Ala145Val	missense	Exon 5 of 14	NP_001337555.1
	BRAT1	NM_001350627.2		c.-92C>T		5_prime_UTR	Exon 4 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.434C>T	p.Ala145Val	missense	Exon 5 of 14	ENSP00000339637.4	Q6PJG6-1
	BRAT1	ENST00000890463.1		c.434C>T	p.Ala145Val	missense	Exon 5 of 16	ENSP00000560522.1
	BRAT1	ENST00000917322.1		c.431C>T	p.Ala144Val	missense	Exon 5 of 16	ENSP00000587381.1

Frequencies

GnomAD3 genomes AF: 0.000902 AC: 136 AN: 150716 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00198

Gnomad ASJ AF: 0.00290

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000191

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.00290

GnomAD2 exomes AF: 0.000818 AC: 178 AN: 217476 AF XY: 0.000746

Gnomad AFR exome AF: 0.000291

Gnomad AMR exome AF: 0.00108

Gnomad ASJ exome AF: 0.00214

Gnomad EAS exome AF: 0.0000604

Gnomad FIN exome AF: 0.000863

Gnomad NFE exome AF: 0.00107

Gnomad OTH exome AF: 0.000196

GnomAD4 exome AF: 0.00114 AC: 1620 AN: 1415576 Hom.: 2 Cov.: 33 AF XY: 0.00109 AC XY: 762 AN XY: 697840

African (AFR) AF: 0.000247 AC: 8 AN: 32372

American (AMR) AF: 0.000888 AC: 37 AN: 41666

Ashkenazi Jewish (ASJ) AF: 0.00283 AC: 69 AN: 24368

East Asian (EAS) AF: 0.0000262 AC: 1 AN: 38174

South Asian (SAS) AF: 0.00 AC: 0 AN: 81948

European-Finnish (FIN) AF: 0.000413 AC: 21 AN: 50908

Middle Eastern (MID) AF: 0.000179 AC: 1 AN: 5588

European-Non Finnish (NFE) AF: 0.00131 AC: 1421 AN: 1082380

Other (OTH) AF: 0.00107 AC: 62 AN: 58172

GnomAD4 genome AF: 0.000902 AC: 136 AN: 150834 Hom.: 0 Cov.: 31 AF XY: 0.00107 AC XY: 79 AN XY: 73722

African (AFR) AF: 0.000147 AC: 6 AN: 40892

American (AMR) AF: 0.00198 AC: 30 AN: 15144

Ashkenazi Jewish (ASJ) AF: 0.00290 AC: 10 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5116

South Asian (SAS) AF: 0.00 AC: 0 AN: 4796

European-Finnish (FIN) AF: 0.000191 AC: 2 AN: 10490

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00121 AC: 82 AN: 67666

Other (OTH) AF: 0.00287 AC: 6 AN: 2094

Alfa AF: 0.00117 Hom.: 0

Bravo AF: 0.000922

ESP6500AA AF: 0.000230 AC: 1

ESP6500EA AF: 0.000947 AC: 8

ExAC AF: 0.000782 AC: 94

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	1	BRAT1-related disorder (1)
-	-	1	Neonatal-onset encephalopathy with rigidity and seizures (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	20
DANN	Benign	0.22
DEOGEN2	Benign	0.0023	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.3
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.028
Sift	Benign	0.25	T
Sift4G	Benign	0.80	T
Polyphen		0.033	B
Vest4		0.29
MVP		0.26
MPC		0.048
ClinPred		0.0061	T
GERP RS		3.3
Varity_R		0.023
gMVP		0.23
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs140833277; hg19: chr7-2583593; COSMIC: COSV100500406; COSMIC: COSV100500406;