rs1085307958

Positions:

• chr7-2544920-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_152743.4(BRAT1):​c.419T>C​(p.Leu140Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. L140L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: BRAT1 NM_152743.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 5.80

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_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 7-2544920-A-G is Pathogenic according to our data. Variant chr7-2544920-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 427101.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRAT1	NM_152743.4	c.419T>C	p.Leu140Pro	missense_variant	4/14	ENST00000340611.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRAT1	ENST00000340611.9	c.419T>C	p.Leu140Pro	missense_variant	4/14	1	NM_152743.4	P1
BRAT1	ENST00000467558.5	n.435T>C		non_coding_transcript_exon_variant	3/10	5
BRAT1	ENST00000469750.5	n.643T>C		non_coding_transcript_exon_variant	4/11	2
BRAT1	ENST00000421712.1	c.283-958T>C		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Neonatal-onset encephalopathy with rigidity and seizures Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 02, 2018

- -

Neurodevelopmental disorder with cerebellar atrophy and with or without seizures Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 02, 2018

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 10, 2015

The L140P variant in the BRAT1 gene has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. The L140P variant was not observed in approximately 6300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L140P variant is a semi-conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The L140P variant is a strong candidate for a disease-causing variant, however the possibility it may be a rare benign variant cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.55	T
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.012	D
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-4.3	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.81		Loss of helix (P = 3e-04);
MVP		0.88
MPC		0.38
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.80
gMVP		0.88

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: rs1085307958; hg19: chr7-2584554;