rs79263074

chr7-2543714-G-Achr7-2543714-G-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

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

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]

ACMG classification

Verdict is Benign. Variant got -9 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 id is 472977.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome 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 gnomad4_exome. There are 403 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRAT1	NM_152743.4	c.679C>T	p.Arg227Cys	missense_variant	5/14	ENST00000340611.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRAT1	ENST00000340611.9	c.679C>T	p.Arg227Cys	missense_variant	5/14	1	NM_152743.4	P1

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

GnomAD3 exomes AF: 0.000415 AC: 98 AN: 236080 Hom.: 0 AF XY: 0.000322 AC XY: 41 AN XY: 127514

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 SAS exome AF: 0.0000358

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0217

Gnomad4 SAS exome AF: 0.0000359

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000825

Gnomad4 OTH exome AF: 0.000119

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

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00675

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000150 Hom.: 0

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

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 21, 2022

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	0.78	N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs79263074; hg19: chr7-2583348; COSMIC: COSV61396339; COSMIC: COSV61396339;