Genetic Variant NM_152743.4:c.604G>T (chr7-2543789-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_152743.4(BRAT1):c.604G>T(p.Val202Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 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. V202I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Consequence

BRAT1
NM_152743.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.25

Publications

0 publications found

Variant links:

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

BRAT1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14018148).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152743.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BRAT1	NM_152743.4	MANE Select	c.604G>T	p.Val202Phe	missense	Exon 5 of 14	NP_689956.2
BRAT1	NM_001350626.2		c.604G>T	p.Val202Phe	missense	Exon 5 of 14	NP_001337555.1
BRAT1	NM_001350627.2		c.79G>T	p.Val27Phe	missense	Exon 4 of 13	NP_001337556.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BRAT1	ENST00000340611.9	TSL:1 MANE Select	c.604G>T	p.Val202Phe	missense	Exon 5 of 14	ENSP00000339637.4
BRAT1	ENST00000421712.1	TSL:3	n.456G>T		non_coding_transcript_exon	Exon 3 of 5	ENSP00000409209.2
BRAT1	ENST00000467558.5	TSL:5	n.620G>T		non_coding_transcript_exon	Exon 4 of 10

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jun 06, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.604G>T (p.V202F) alteration is located in exon 5 (coding exon 4) of the BRAT1 gene. This alteration results from a G to T substitution at nucleotide position 604, causing the valine (V) at amino acid position 202 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.26

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.40

CADD

Benign

1.0

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.046

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.060

LIST_S2

Benign

0.74

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.8

PhyloP100

-1.3

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.7

REVEL

Benign

0.23

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.044

Polyphen

0.66

Vest4

0.34

MutPred

0.18

Loss of ubiquitination at K197 (P = 0.1355)

MVP

0.30

MPC

0.18

ClinPred

0.66

GERP RS

-10

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.060

gMVP

0.54

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over