rs151317339

Variant names:

• chr7-2543244-T-C
• rs151317339
• NM_152743.4:c.883A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-2543244-T-C
• chr7-2543244-T-A
• chr7-2543244-T-G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_152743.4(BRAT1):​c.883A>G​(p.Met295Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000535 in 1,610,432 control chromosomes in the GnomAD database, including 3 homozygotes. 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M295K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (3 hom.)
• Consequence: BRAT1 NM_152743.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.734
• Publications: 2 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014736861).
• BP6: Variant 7-2543244-T-C is Benign according to our data. Variant chr7-2543244-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 540153.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

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.883A>G	p.Met295Val	missense	Exon 6 of 14	NP_689956.2	Q6PJG6-1
	BRAT1	NM_001350626.2		c.883A>G	p.Met295Val	missense	Exon 6 of 14	NP_001337555.1
	BRAT1	NM_001350627.2		c.358A>G	p.Met120Val	missense	Exon 5 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.883A>G	p.Met295Val	missense	Exon 6 of 14	ENSP00000339637.4	Q6PJG6-1
	BRAT1	ENST00000890463.1		c.883A>G	p.Met295Val	missense	Exon 6 of 16	ENSP00000560522.1
	BRAT1	ENST00000917322.1		c.880A>G	p.Met294Val	missense	Exon 6 of 16	ENSP00000587381.1

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 57 AN: 152022 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000230 AC: 57 AN: 248196 AF XY: 0.000253

Gnomad AFR exome AF: 0.000372

Gnomad AMR exome AF: 0.0000588

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000419

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000551 AC: 804 AN: 1458292 Hom.: 3 Cov.: 31 AF XY: 0.000536 AC XY: 389 AN XY: 725254

African (AFR) AF: 0.000210 AC: 7 AN: 33324

American (AMR) AF: 0.0000677 AC: 3 AN: 44308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26028

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39430

South Asian (SAS) AF: 0.00 AC: 0 AN: 85984

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52802

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5746

European-Non Finnish (NFE) AF: 0.000698 AC: 775 AN: 1110468

Other (OTH) AF: 0.000282 AC: 17 AN: 60202

GnomAD4 genome AF: 0.000375 AC: 57 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74386

African (AFR) AF: 0.000289 AC: 12 AN: 41508

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.000647 AC: 44 AN: 67980

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000458 Hom.: 0

Bravo AF: 0.000348

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.000600

EpiControl AF: 0.000714

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	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)
-	1	-	Neurodevelopmental disorder with cerebellar atrophy and with or without seizures (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	2.4
DANN	Benign	0.41
DEOGEN2	Benign	0.00093	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0056	N
LIST_S2	Benign	0.22	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.69	N
PhyloP100		0.73
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.076
Sift	Benign	0.50	T
Sift4G	Benign	0.61	T
Polyphen		0.0	B
Vest4		0.091
MVP		0.32
MPC		0.046
ClinPred		0.0047	T
GERP RS		4.0
Varity_R		0.037
gMVP		0.17
Mutation Taster		=98/2	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: rs151317339; hg19: chr7-2582878;