7-2538109-G-A

Variant names:

• chr7-2538109-G-A
• rs779616647
• NM_152743.4:c.2426C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152743.4(BRAT1):​c.2426C>T​(p.Thr809Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000695 in 1,439,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: BRAT1 NM_152743.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.66

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20908874).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAT1	NM_152743.4	c.2426C>T	p.Thr809Met	missense_variant	Exon 14 of 14	ENST00000340611.9	NP_689956.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAT1	ENST00000340611.9	c.2426C>T	p.Thr809Met	missense_variant	Exon 14 of 14	1	NM_152743.4	ENSP00000339637.4
BRAT1	ENST00000467558.5	n.4212C>T		non_coding_transcript_exon_variant	Exon 10 of 10	5
BRAT1	ENST00000469750.5	n.4998C>T		non_coding_transcript_exon_variant	Exon 11 of 11	2
BRAT1	ENST00000493232.5	n.5132C>T		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000126 AC: 3 AN: 237428 Hom.: 0 AF XY: 0.0000154 AC XY: 2 AN XY: 130188

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000300

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000565

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000943

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000695 AC: 10 AN: 1439316 Hom.: 0 Cov.: 31 AF XY: 0.00000843 AC XY: 6 AN XY: 711894

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000821

Gnomad4 OTH exome AF: 0.0000169

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

ExAC AF: 0.0000166 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neonatal-onset encephalopathy with rigidity and seizures Uncertain:1

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 809 of the BRAT1 protein (p.Thr809Met). This variant is present in population databases (rs779616647, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with BRAT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 860591). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRAT1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.049	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.18
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.82	P
Vest4		0.24
MutPred		0.54		Loss of solvent accessibility (P = 0.0769);
MVP		0.37
MPC		0.083
ClinPred		0.33	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.42

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

Publications

LitVar

Other links and lift over

dbSNP: rs779616647; hg19: chr7-2577743;