7-2539852-G-C

Variant names:

• chr7-2539852-G-C
• rs772904982
• NM_152743.4:c.1432C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_152743.4(BRAT1):​c.1432C>G​(p.Leu478Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000967 in 1,447,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000097 (0 hom.)
• Consequence: BRAT1 NM_152743.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.38
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAT1	NM_152743.4	c.1432C>G	p.Leu478Val	missense_variant	Exon 11 of 14	ENST00000340611.9	NP_689956.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAT1	ENST00000340611.9	c.1432C>G	p.Leu478Val	missense_variant	Exon 11 of 14	1	NM_152743.4	ENSP00000339637.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000890 AC: 2 AN: 224844 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000982

Gnomad OTH exome AF: 0.000184

GnomAD4 exome AF: 0.00000967 AC: 14 AN: 1447628 Hom.: 0 Cov.: 32 AF XY: 0.0000139 AC XY: 10 AN XY: 719518

African (AFR) AF: 0.00 AC: 0 AN: 32926

American (AMR) AF: 0.00 AC: 0 AN: 41662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25278

East Asian (EAS) AF: 0.00 AC: 0 AN: 39398

South Asian (SAS) AF: 0.00 AC: 0 AN: 83944

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.0000127 AC: 14 AN: 1106444

Other (OTH) AF: 0.00 AC: 0 AN: 59664

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000573 Hom.: 0

Bravo AF: 0.0000189

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

Nov 19, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with BRAT1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with valine at codon 478 of the BRAT1 protein (p.Leu478Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0060	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.4
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.083
Sift	Uncertain	0.014	D
Sift4G	Benign	0.085	T
Polyphen		0.88	P
Vest4		0.48
MutPred		0.26		Gain of MoRF binding (P = 0.082);
MVP		0.30
MPC		0.12
ClinPred		0.40	T
GERP RS		4.3
Varity_R		0.13
gMVP		0.27
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.73		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.73		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs772904982; hg19: chr7-2579486;