rs186448943

Variant names:

• chr7-2538563-C-T
• rs186448943
• NM_152743.4:c.1972G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_152743.4(BRAT1):​c.1972G>A​(p.Ala658Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000296 in 1,600,020 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 0.00029 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00030 (0 hom.)
• Consequence: BRAT1 NM_152743.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.24
• Publications: 1 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19438404).

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.1972G>A	p.Ala658Thr	missense	Exon 14 of 14	NP_689956.2	Q6PJG6-1
	BRAT1	NM_001350626.2		c.2152G>A	p.Ala718Thr	missense	Exon 14 of 14	NP_001337555.1
	BRAT1	NM_001350627.2		c.1447G>A	p.Ala483Thr	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.1972G>A	p.Ala658Thr	missense	Exon 14 of 14	ENSP00000339637.4	Q6PJG6-1
	BRAT1	ENST00000890463.1		c.2209G>A	p.Ala737Thr	missense	Exon 16 of 16	ENSP00000560522.1
	BRAT1	ENST00000917322.1		c.2206G>A	p.Ala736Thr	missense	Exon 16 of 16	ENSP00000587381.1

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152182 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

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: 0.000162

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000123 AC: 28 AN: 227524 AF XY: 0.000111

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000267

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000174

Gnomad OTH exome AF: 0.000175

GnomAD4 exome AF: 0.000297 AC: 430 AN: 1447720 Hom.: 0 Cov.: 59 AF XY: 0.000289 AC XY: 208 AN XY: 720372

African (AFR) AF: 0.00 AC: 0 AN: 33386

American (AMR) AF: 0.000406 AC: 18 AN: 44332

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39542

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86002

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42770

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.000352 AC: 391 AN: 1109860

Other (OTH) AF: 0.000333 AC: 20 AN: 60060

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152300 Hom.: 0 Cov.: 34 AF XY: 0.000269 AC XY: 20 AN XY: 74480

African (AFR) AF: 0.000144 AC: 6 AN: 41574

American (AMR) AF: 0.00170 AC: 26 AN: 15310

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68010

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000277 Hom.: 0

Bravo AF: 0.000434

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.0000998 AC: 12

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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	0.27
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.074	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.19	T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.2
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.29
Sift	Benign	0.030	D
Sift4G	Uncertain	0.018	D
Polyphen		0.99	D
Vest4		0.40
MVP		0.64
MPC		0.28
ClinPred		0.27	T
GERP RS		4.6
Varity_R		0.080
gMVP		0.32
Mutation Taster		=94/6	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: rs186448943; hg19: chr7-2578197;