rs61753094

Variant names:

• chr7-2538707-G-A
• rs61753094
• NM_152743.4:c.1828C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-2538707-G-A
• chr7-2538707-G-C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The NM_001350626.2(BRAT1):​c.2008C>T​(p.Arg670Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,598,424 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R670Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0024 (8 hom.)
• Consequence: BRAT1 NM_001350626.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 0.993
• Publications: 9 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2974794).
• BP6: Variant 7-2538707-G-A is Benign according to our data. Variant chr7-2538707-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 446895.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001350626.2. 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.1828C>T	p.Arg610Trp	missense	Exon 14 of 14	NP_689956.2
	BRAT1	NM_001350626.2		c.2008C>T	p.Arg670Trp	missense	Exon 14 of 14	NP_001337555.1
	BRAT1	NM_001350627.2		c.1303C>T	p.Arg435Trp	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.1828C>T	p.Arg610Trp	missense	Exon 14 of 14	ENSP00000339637.4
	BRAT1	ENST00000890463.1		c.2065C>T	p.Arg689Trp	missense	Exon 16 of 16	ENSP00000560522.1
	BRAT1	ENST00000917322.1		c.2062C>T	p.Arg688Trp	missense	Exon 16 of 16	ENSP00000587381.1

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 217 AN: 152228 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00270

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00124 AC: 288 AN: 232480 AF XY: 0.00119

Gnomad AFR exome AF: 0.000413

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00252

Gnomad OTH exome AF: 0.000682

GnomAD4 exome AF: 0.00239 AC: 3454 AN: 1446078 Hom.: 8 Cov.: 68 AF XY: 0.00233 AC XY: 1674 AN XY: 719764

African (AFR) AF: 0.000359 AC: 12 AN: 33472

American (AMR) AF: 0.000179 AC: 8 AN: 44716

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

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

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.000395 AC: 15 AN: 37942

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00298 AC: 3316 AN: 1111822

Other (OTH) AF: 0.00161 AC: 97 AN: 60284

GnomAD4 genome AF: 0.00142 AC: 217 AN: 152346 Hom.: 1 Cov.: 34 AF XY: 0.00138 AC XY: 103 AN XY: 74508

African (AFR) AF: 0.000577 AC: 24 AN: 41576

American (AMR) AF: 0.000261 AC: 4 AN: 15310

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

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

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

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00270 AC: 184 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00186 Hom.: 0

Bravo AF: 0.00142

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000931 AC: 4

ESP6500EA AF: 0.00166 AC: 14

ExAC AF: 0.00126 AC: 151

EpiCase AF: 0.00185

EpiControl AF: 0.00207

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	not provided (4)
-	-	2	BRAT1-related disorder (2)
-	-	1	Neonatal-onset encephalopathy with rigidity and seizures (1)
-	1	-	Neonatal-onset encephalopathy with rigidity and seizures;C4748032:Neurodevelopmental disorder with cerebellar atrophy and with or without seizures (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Pathogenic	0.20
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.30	T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.99
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MVP		0.67
MPC		0.32
ClinPred		0.10	T
GERP RS		-1.9
Varity_R		0.53
gMVP		0.73
Mutation Taster		=91/9	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: rs61753094; hg19: chr7-2578341; COSMIC: COSV61396929; COSMIC: COSV61396929;