rs1554298600

Positions:

• chr7-2554398-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152743.4(BRAT1):​c.34C>G​(p.Leu12Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: 0.0000014 (0 hom.)
• Consequence: BRAT1 NM_152743.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.34

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06469607).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRAT1	NM_152743.4	c.34C>G	p.Leu12Val	missense_variant	2/14	ENST00000340611.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRAT1	ENST00000340611.9	c.34C>G	p.Leu12Val	missense_variant	2/14	1	NM_152743.4	P1
BRAT1	ENST00000467558.5	n.50C>G		non_coding_transcript_exon_variant	1/10	5
BRAT1	ENST00000469750.5	n.258C>G		non_coding_transcript_exon_variant	2/11	2
BRAT1	ENST00000421712.1	c.34C>G	p.Leu12Val	missense_variant, NMD_transcript_variant	1/5	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461556 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727082

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neonatal-onset encephalopathy with rigidity and seizures Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 13, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 05, 2022	Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 540155). This variant has not been reported in the literature in individuals affected with BRAT1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 12 of the BRAT1 protein (p.Leu12Val). 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	0.076
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	9.0
DANN	Benign	0.67
DEOGEN2	Benign	0.0013	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.22	N
MutationTaster	Benign	0.88	N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.13
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0090	B
Vest4		0.20
MutPred		0.25		Gain of sheet (P = 0.0125);
MVP		0.51
MPC		0.050
ClinPred		0.055	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.038
gMVP		0.22

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: rs1554298600; hg19: chr7-2594032;