rs373020561

Variant names:

• chr7-2542123-G-A
• rs373020561
• NM_152743.4:c.1012C>T
• BRAT1 p.Pro338Ser

Your query was ambiguous. Multiple possible variants found:

• chr7-2542123-G-A
• chr7-2542123-G-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152743.4(BRAT1):​c.1012C>T​(p.Pro338Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000647 in 1,546,158 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P338A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: BRAT1 NM_152743.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045410186).

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>T	p.Pro338Ser	missense	Exon 7 of 14	NP_689956.2	Q6PJG6-1
	BRAT1	NM_001350626.2		c.1012C>T	p.Pro338Ser	missense	Exon 7 of 14	NP_001337555.1
	BRAT1	NM_001350627.2		c.487C>T	p.Pro163Ser	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>T	p.Pro338Ser	missense	Exon 7 of 14	ENSP00000339637.4	Q6PJG6-1
	BRAT1	ENST00000890463.1		c.1012C>T	p.Pro338Ser	missense	Exon 7 of 16	ENSP00000560522.1
	BRAT1	ENST00000917322.1		c.1009C>T	p.Pro337Ser	missense	Exon 7 of 16	ENSP00000587381.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000127 AC: 2 AN: 157716 AF XY: 0.00

Gnomad AFR exome AF: 0.000208

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1393934 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 688062

African (AFR) AF: 0.0000317 AC: 1 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: 0.00 AC: 0 AN: 77868

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5376

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078536

Other (OTH) AF: 0.0000174 AC: 1 AN: 57454

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74418

African (AFR) AF: 0.000169 AC: 7 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: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68000

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

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.0000567

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	4.3
DANN	Benign	0.58
DEOGEN2	Benign	0.0030	T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	0.80	N
PhyloP100		-0.19
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.065
Sift	Benign	0.32	T
Sift4G	Benign	0.31	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.036
gMVP		0.18
Mutation Taster		=99/1	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

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;

COSMIC: COSV61397358;

COSMIC: COSV61397358;