rs532881368

Variant names:

• chr7-2538731-C-T
• rs532881368
• NM_152743.4:c.1804G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NM_152743.4(BRAT1):​c.1804G>A​(p.Val602Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000976 in 1,598,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V602V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: BRAT1 NM_152743.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: -0.539
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026745826).
• BP6: Variant 7-2538731-C-T is Benign according to our data. Variant chr7-2538731-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 540177.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAT1	NM_152743.4	MANE Select	c.1804G>A	p.Val602Ile	missense	Exon 14 of 14	NP_689956.2
	BRAT1	NM_001350626.2		c.1984G>A	p.Val662Ile	missense	Exon 14 of 14	NP_001337555.1
	BRAT1	NM_001350627.2		c.1279G>A	p.Val427Ile	missense	Exon 13 of 13	NP_001337556.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAT1	ENST00000340611.9	TSL:1 MANE Select	c.1804G>A	p.Val602Ile	missense	Exon 14 of 14	ENSP00000339637.4
	BRAT1	ENST00000890463.1		c.2041G>A	p.Val681Ile	missense	Exon 16 of 16	ENSP00000560522.1
	BRAT1	ENST00000917322.1		c.2038G>A	p.Val680Ile	missense	Exon 16 of 16	ENSP00000587381.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152226 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000112 AC: 26 AN: 232358 AF XY: 0.000141

Gnomad AFR exome AF: 0.000138

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000857

Gnomad NFE exome AF: 0.0000833

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000102 AC: 148 AN: 1446060 Hom.: 0 Cov.: 65 AF XY: 0.000113 AC XY: 81 AN XY: 719746

African (AFR) AF: 0.000149 AC: 5 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.000568 AC: 49 AN: 86258

European-Finnish (FIN) AF: 0.0000791 AC: 3 AN: 37914

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.0000756 AC: 84 AN: 1111834

Other (OTH) AF: 0.0000829 AC: 5 AN: 60282

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152344 Hom.: 0 Cov.: 34 AF XY: 0.0000671 AC XY: 5 AN XY: 74500

African (AFR) AF: 0.0000481 AC: 2 AN: 41586

American (AMR) AF: 0.00 AC: 0 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.000108 AC: 13

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	-	1	Neonatal-onset encephalopathy with rigidity and seizures (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.71
DANN	Benign	0.87
DEOGEN2	Benign	0.0021	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0066	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.54
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.050
Sift	Benign	0.39	T
Sift4G	Benign	0.14	T
Polyphen		0.028	B
Vest4		0.083
MutPred		0.19		Gain of catalytic residue at S604 (P = 0.2239)
MVP		0.44
MPC		0.041
ClinPred		0.0058	T
GERP RS		-1.0
Varity_R		0.011
gMVP		0.071
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs532881368; hg19: chr7-2578365;