chr7-2541423-C-G

Position:

• chr7-2541423-C-G

Variant summary

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

The NM_152743.4(BRAT1):​c.1196G>C​(p.Arg399Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R399Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRAT1 NM_152743.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.24

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRAT1	NM_152743.4	c.1196G>C	p.Arg399Pro	missense_variant	9/14	ENST00000340611.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRAT1	ENST00000340611.9	c.1196G>C	p.Arg399Pro	missense_variant	9/14	1	NM_152743.4	P1
BRAT1	ENST00000467558.5	n.1478G>C		non_coding_transcript_exon_variant	7/10	5
BRAT1	ENST00000469750.5	n.2678G>C		non_coding_transcript_exon_variant	7/11	2
BRAT1	ENST00000493232.5	n.2597G>C		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 14, 2020

This sequence change replaces arginine with proline at codon 399 of the BRAT1 protein (p.Arg399Pro). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRAT1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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	Pathogenic	0.62
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	12
DANN	Benign	0.97
DEOGEN2	Benign	0.089	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	1.9	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.037	D
Polyphen		0.97	D
Vest4		0.61
MutPred		0.67		Gain of glycosylation at T396 (P = 0.0147);
MVP		0.57
MPC		0.24
ClinPred		0.98	D
GERP RS		-3.6
Varity_R		0.44
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-2581057;