rs35659709

Variant names:

• chr7-2541442-C-T
• rs35659709
• NM_152743.4:c.1177G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-2541442-C-T
• chr7-2541442-C-A
• chr7-2541442-C-G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_152743.4(BRAT1):​c.1177G>A​(p.Ala393Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000744 in 1,573,444 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000077 (0 hom.)
• Consequence: BRAT1 NM_152743.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 3.30
• 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: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3835752).

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.1177G>A	p.Ala393Thr	missense	Exon 9 of 14	NP_689956.2	Q6PJG6-1
	BRAT1	NM_001350626.2		c.1177G>A	p.Ala393Thr	missense	Exon 9 of 14	NP_001337555.1
	BRAT1	NM_001350627.2		c.652G>A	p.Ala218Thr	missense	Exon 8 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.1177G>A	p.Ala393Thr	missense	Exon 9 of 14	ENSP00000339637.4	Q6PJG6-1
	BRAT1	ENST00000890463.1		c.1177G>A	p.Ala393Thr	missense	Exon 9 of 16	ENSP00000560522.1
	BRAT1	ENST00000917322.1		c.1174G>A	p.Ala392Thr	missense	Exon 9 of 16	ENSP00000587381.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000840 AC: 15 AN: 178494 AF XY: 0.000103

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000757

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000588

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000682

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000767 AC: 109 AN: 1421196 Hom.: 0 Cov.: 33 AF XY: 0.0000782 AC XY: 55 AN XY: 703642

African (AFR) AF: 0.00 AC: 0 AN: 32756

American (AMR) AF: 0.000106 AC: 4 AN: 37888

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25320

East Asian (EAS) AF: 0.000211 AC: 8 AN: 37904

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 82200

European-Finnish (FIN) AF: 0.0000409 AC: 2 AN: 48878

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4948

European-Non Finnish (NFE) AF: 0.0000842 AC: 92 AN: 1092484

Other (OTH) AF: 0.0000340 AC: 2 AN: 58818

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74448

African (AFR) AF: 0.00 AC: 0 AN: 41558

American (AMR) AF: 0.00 AC: 0 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

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: 0.000118 AC: 8 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.0000592 AC: 7

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0085	T
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.3
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.30
Sift	Benign	0.040	D
Sift4G	Benign	0.073	T
Polyphen		1.0	D
Vest4		0.52
MVP		0.78
MPC		0.15
ClinPred		0.17	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.077
gMVP		0.38
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35659709; hg19: chr7-2581076;