rs138585448

Variant names:

• chr7-2544978-T-G
• rs138585448
• NM_152743.4:c.361A>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BP6_Very_Strong

The NM_152743.4(BRAT1):​c.361A>C​(p.Ser121Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000161 in 1,568,368 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S121S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00084 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000088 (0 hom.)
• Consequence: BRAT1 NM_152743.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.66
• 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.078555614).
• BP6: Variant 7-2544978-T-G is Benign according to our data. Variant chr7-2544978-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 472967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.361A>C	p.Ser121Arg	missense	Exon 4 of 14	NP_689956.2	Q6PJG6-1
	BRAT1	NM_001350626.2		c.361A>C	p.Ser121Arg	missense	Exon 4 of 14	NP_001337555.1
	BRAT1	NM_001350627.2		c.-95-1016A>C		intron	N/A	NP_001337556.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAT1	ENST00000340611.9	TSL:1 MANE Select	c.361A>C	p.Ser121Arg	missense	Exon 4 of 14	ENSP00000339637.4	Q6PJG6-1
	BRAT1	ENST00000890463.1		c.361A>C	p.Ser121Arg	missense	Exon 4 of 16	ENSP00000560522.1
	BRAT1	ENST00000917322.1		c.358A>C	p.Ser120Arg	missense	Exon 4 of 16	ENSP00000587381.1

Frequencies

GnomAD3 genomes AF: 0.000841 AC: 128 AN: 152174 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

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: 0.000205 AC: 37 AN: 180178 AF XY: 0.000186

Gnomad AFR exome AF: 0.00283

Gnomad AMR exome AF: 0.000190

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000132

Gnomad OTH exome AF: 0.000212

GnomAD4 exome AF: 0.0000876 AC: 124 AN: 1416076 Hom.: 0 Cov.: 31 AF XY: 0.0000800 AC XY: 56 AN XY: 700000

African (AFR) AF: 0.00294 AC: 96 AN: 32684

American (AMR) AF: 0.000188 AC: 7 AN: 37164

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24998

East Asian (EAS) AF: 0.00 AC: 0 AN: 37818

South Asian (SAS) AF: 0.00 AC: 0 AN: 80548

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49416

Middle Eastern (MID) AF: 0.000707 AC: 4 AN: 5660

European-Non Finnish (NFE) AF: 0.00000275 AC: 3 AN: 1089050

Other (OTH) AF: 0.000238 AC: 14 AN: 58738

GnomAD4 genome AF: 0.000840 AC: 128 AN: 152292 Hom.: 0 Cov.: 30 AF XY: 0.000859 AC XY: 64 AN XY: 74482

African (AFR) AF: 0.00289 AC: 120 AN: 41572

American (AMR) AF: 0.000523 AC: 8 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

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: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000295 Hom.: 0

Bravo AF: 0.000926

ESP6500AA AF: 0.00253 AC: 11

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.000185 AC: 22

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	BRAT1-related disorder (1)
-	-	1	Neonatal-onset encephalopathy with rigidity and seizures (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.019	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.079	T
MetaSVM	Uncertain	0.32	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.7
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.59
Sift	Benign	0.13	T
Sift4G	Benign	0.40	T
Polyphen		1.0	D
Vest4		0.87
MutPred		0.33		Gain of MoRF binding (P = 0.0273)
MVP		0.89
MPC		0.094
ClinPred		0.034	T
GERP RS		5.6
Varity_R		0.29
gMVP		0.70
Mutation Taster		=80/20	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: rs138585448; hg19: chr7-2584612;