rs140802292

Variant names:

• chr7-2538388-G-A
• rs140802292
• NM_152743.4:c.2147C>T

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.2147C>T​(p.Ala716Val) variant causes a missense change. The variant allele was found at a frequency of 0.000172 in 1,613,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. A716A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: BRAT1 NM_152743.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 4.32
• Publications: 7 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, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• 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=0.024533004).
• BP6: Variant 7-2538388-G-A is Benign according to our data. Variant chr7-2538388-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 540163.

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.2147C>T	p.Ala716Val	missense	Exon 14 of 14	NP_689956.2	Q6PJG6-1
	BRAT1	NM_001350626.2		c.2327C>T	p.Ala776Val	missense	Exon 14 of 14	NP_001337555.1
	BRAT1	NM_001350627.2		c.1622C>T	p.Ala541Val	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.2147C>T	p.Ala716Val	missense	Exon 14 of 14	ENSP00000339637.4	Q6PJG6-1
	BRAT1	ENST00000890463.1		c.2384C>T	p.Ala795Val	missense	Exon 16 of 16	ENSP00000560522.1
	BRAT1	ENST00000917322.1		c.2381C>T	p.Ala794Val	missense	Exon 16 of 16	ENSP00000587381.1

Frequencies

GnomAD3 genomes AF: 0.000716 AC: 109 AN: 152224 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00229

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000252 AC: 63 AN: 250216 AF XY: 0.000229

Gnomad AFR exome AF: 0.00223

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000443

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000115 AC: 168 AN: 1461222 Hom.: 0 Cov.: 63 AF XY: 0.000113 AC XY: 82 AN XY: 726942

African (AFR) AF: 0.00185 AC: 62 AN: 33472

American (AMR) AF: 0.000559 AC: 25 AN: 44724

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52862

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000630 AC: 70 AN: 1111934

Other (OTH) AF: 0.000116 AC: 7 AN: 60384

GnomAD4 genome AF: 0.000715 AC: 109 AN: 152342 Hom.: 0 Cov.: 34 AF XY: 0.000765 AC XY: 57 AN XY: 74494

African (AFR) AF: 0.00228 AC: 95 AN: 41576

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68032

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.000319 Hom.: 0

Bravo AF: 0.000740

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000272 AC: 33

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Neonatal-onset encephalopathy with rigidity and seizures (2)
-	2	-	not provided (2)
-	-	1	BRAT1-related disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.012	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.66
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.85	T
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.025	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.3
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.22
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.57
MVP		0.48
MPC		0.32
ClinPred		0.050	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.39
Mutation Taster		=86/14	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: rs140802292; hg19: chr7-2578022; COSMIC: COSV61394470; COSMIC: COSV61394470;