7-2543714-G-A

Variant names:

• chr7-2543714-G-A
• rs79263074
• NM_152743.4:c.679C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_152743.4(BRAT1):​c.679C>T​(p.Arg227Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000571 in 1,582,498 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts 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. R227H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00061 (17 hom.)
• Consequence: BRAT1 NM_152743.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.89
• 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, 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010544121).
• BP6: Variant 7-2543714-G-A is Benign according to our data. Variant chr7-2543714-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 472977.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.000606 (866/1430166) while in subpopulation EAS AF = 0.0217 (847/38984). AF 95% confidence interval is 0.0205. There are 17 homozygotes in GnomAdExome4. There are 403 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 17 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.679C>T	p.Arg227Cys	missense	Exon 5 of 14	NP_689956.2
	BRAT1	NM_001350626.2		c.679C>T	p.Arg227Cys	missense	Exon 5 of 14	NP_001337555.1
	BRAT1	NM_001350627.2		c.154C>T	p.Arg52Cys	missense	Exon 4 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.679C>T	p.Arg227Cys	missense	Exon 5 of 14	ENSP00000339637.4
	BRAT1	ENST00000421712.1	TSL:3	n.*24C>T		non_coding_transcript_exon	Exon 3 of 5	ENSP00000409209.2
	BRAT1	ENST00000467558.5	TSL:5	n.695C>T		non_coding_transcript_exon	Exon 4 of 10

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152214 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00674

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000415 AC: 98 AN: 236080 AF XY: 0.000322

Gnomad AFR exome AF: 0.0000625

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00527

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000944

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000606 AC: 866 AN: 1430166 Hom.: 17 Cov.: 33 AF XY: 0.000571 AC XY: 403 AN XY: 706138

African (AFR) AF: 0.00 AC: 0 AN: 32960

American (AMR) AF: 0.00 AC: 0 AN: 43150

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24786

East Asian (EAS) AF: 0.0217 AC: 847 AN: 38984

South Asian (SAS) AF: 0.0000359 AC: 3 AN: 83514

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51792

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5648

European-Non Finnish (NFE) AF: 0.00000825 AC: 9 AN: 1090468

Other (OTH) AF: 0.000119 AC: 7 AN: 58864

GnomAD4 genome AF: 0.000249 AC: 38 AN: 152332 Hom.: 0 Cov.: 31 AF XY: 0.000309 AC XY: 23 AN XY: 74490

African (AFR) AF: 0.0000721 AC: 3 AN: 41582

American (AMR) AF: 0.00 AC: 0 AN: 15300

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

East Asian (EAS) AF: 0.00675 AC: 35 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000529 Hom.: 2

Bravo AF: 0.0000831

ExAC AF: 0.000527 AC: 64

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Feb 21, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported previously in an individual with Dravet syndrome; however, a second BRAT1 variant was not identified, and the patient was found to have a variant in the SCN1A gene (Kim et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29295803)

Neonatal-onset encephalopathy with rigidity and seizures Benign:1

Dec 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.9
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.44
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.048	D
Polyphen		1.0	D
Vest4		0.16
MVP		0.93
MPC		0.30
ClinPred		0.081	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.093
gMVP		0.14
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs79263074; hg19: chr7-2583348; COSMIC: COSV61396339; COSMIC: COSV61396339;