chr7-2544957-G-A

Variant names:

• chr7-2544957-G-A
• rs770461144
• NM_152743.4:c.382C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_152743.4(BRAT1):​c.382C>T​(p.Arg128Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000615 in 1,560,552 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R128H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000064 (0 hom.)
• Consequence: BRAT1 NM_152743.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.189
• 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_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0919548).

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.382C>T	p.Arg128Cys	missense	Exon 4 of 14	NP_689956.2
	BRAT1	NM_001350626.2		c.382C>T	p.Arg128Cys	missense	Exon 4 of 14	NP_001337555.1
	BRAT1	NR_146879.2		n.441C>T		non_coding_transcript_exon	Exon 4 of 15

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAT1	ENST00000340611.9	TSL:1 MANE Select	c.382C>T	p.Arg128Cys	missense	Exon 4 of 14	ENSP00000339637.4
	BRAT1	ENST00000467558.5	TSL:5	n.398C>T		non_coding_transcript_exon	Exon 3 of 10
	BRAT1	ENST00000469750.5	TSL:2	n.606C>T		non_coding_transcript_exon	Exon 4 of 11

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152202 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000538 AC: 9 AN: 167156 AF XY: 0.0000560

Gnomad AFR exome AF: 0.000103

Gnomad AMR exome AF: 0.000198

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000149

Gnomad OTH exome AF: 0.000220

GnomAD4 exome AF: 0.0000639 AC: 90 AN: 1408232 Hom.: 0 Cov.: 31 AF XY: 0.0000575 AC XY: 40 AN XY: 695468

African (AFR) AF: 0.0000925 AC: 3 AN: 32448

American (AMR) AF: 0.000249 AC: 9 AN: 36210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25114

East Asian (EAS) AF: 0.00 AC: 0 AN: 37146

South Asian (SAS) AF: 0.0000250 AC: 2 AN: 79982

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48734

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5570

European-Non Finnish (NFE) AF: 0.0000645 AC: 70 AN: 1084620

Other (OTH) AF: 0.000103 AC: 6 AN: 58408

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152320 Hom.: 0 Cov.: 30 AF XY: 0.0000269 AC XY: 2 AN XY: 74486

African (AFR) AF: 0.0000241 AC: 1 AN: 41574

American (AMR) AF: 0.000131 AC: 2 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68016

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000172 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Neonatal-onset encephalopathy with rigidity and seizures (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0034	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.092	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.60	N
PhyloP100		0.19
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.10
Sift	Benign	0.18	T
Sift4G	Benign	0.18	T
Polyphen		0.014	B
Vest4		0.11
MutPred		0.28		Loss of MoRF binding (P = 0.0021)
MVP		0.57
MPC		0.058
ClinPred		0.021	T
GERP RS		-0.73
Varity_R		0.036
gMVP		0.24
Mutation Taster		=97/3	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: rs770461144; hg19: chr7-2584591; COSMIC: COSV100500304; COSMIC: COSV100500304;