7-2542123-G-C

Variant names:

• chr7-2542123-G-C
• rs373020561
• NM_152743.4:c.1012C>G
• BRAT1 p.Pro338Ala

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_152743.4(BRAT1):​c.1012C>G​(p.Pro338Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000524 in 1,546,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P338S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: BRAT1 NM_152743.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.189
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P, Orphanet
• neurodevelopmental disorder with cerebellar atrophy and with or without seizures

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics, ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.051510215).

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.1012C>G	p.Pro338Ala	missense	Exon 7 of 14	NP_689956.2	Q6PJG6-1
	BRAT1	NM_001350626.2		c.1012C>G	p.Pro338Ala	missense	Exon 7 of 14	NP_001337555.1
	BRAT1	NM_001350627.2		c.487C>G	p.Pro163Ala	missense	Exon 6 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.1012C>G	p.Pro338Ala	missense	Exon 7 of 14	ENSP00000339637.4	Q6PJG6-1
	BRAT1	ENST00000890463.1		c.1012C>G	p.Pro338Ala	missense	Exon 7 of 16	ENSP00000560522.1
	BRAT1	ENST00000917322.1		c.1009C>G	p.Pro337Ala	missense	Exon 7 of 16	ENSP00000587381.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000824 AC: 13 AN: 157716 AF XY: 0.0000591

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000435

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000933

Gnomad OTH exome AF: 0.00122

GnomAD4 exome AF: 0.0000560 AC: 78 AN: 1393934 Hom.: 0 Cov.: 32 AF XY: 0.0000625 AC XY: 43 AN XY: 688062

African (AFR) AF: 0.0000635 AC: 2 AN: 31508

American (AMR) AF: 0.00 AC: 0 AN: 33854

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23734

East Asian (EAS) AF: 0.00 AC: 0 AN: 36930

South Asian (SAS) AF: 0.000116 AC: 9 AN: 77868

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48674

Middle Eastern (MID) AF: 0.00484 AC: 26 AN: 5376

European-Non Finnish (NFE) AF: 0.0000287 AC: 31 AN: 1078536

Other (OTH) AF: 0.000174 AC: 10 AN: 57454

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74418

African (AFR) AF: 0.0000241 AC: 1 AN: 41540

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000265 Hom.: 1

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	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	0.056
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	0.38
DANN	Benign	0.60
DEOGEN2	Benign	0.0026	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.61	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.19
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.096
Sift	Benign	0.38	T
Sift4G	Benign	0.31	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.033
gMVP		0.12
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs373020561;

hg19: chr7-2581757;