rs760510041

Variant names:

• chr7-2541017-G-A
• rs760510041
• NM_152743.4:c.1357C>T

Your query was ambiguous. Multiple possible variants found:

• chr7-2541017-G-A
• chr7-2541017-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_152743.4(BRAT1):​c.1357C>T​(p.Leu453Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000613 in 1,565,320 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000061 (0 hom.)
• Consequence: BRAT1 NM_152743.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.54
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1357C>T	p.Leu453Phe	missense	Exon 10 of 14	NP_689956.2	Q6PJG6-1
	BRAT1	NM_001350626.2		c.1357C>T	p.Leu453Phe	missense	Exon 10 of 14	NP_001337555.1
	BRAT1	NM_001350627.2		c.832C>T	p.Leu278Phe	missense	Exon 9 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.1357C>T	p.Leu453Phe	missense	Exon 10 of 14	ENSP00000339637.4	Q6PJG6-1
	BRAT1	ENST00000890463.1		c.1357C>T	p.Leu453Phe	missense	Exon 10 of 16	ENSP00000560522.1
	BRAT1	ENST00000917322.1		c.1354C>T	p.Leu452Phe	missense	Exon 10 of 16	ENSP00000587381.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152164 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000457 AC: 9 AN: 196918 AF XY: 0.0000457

Gnomad AFR exome AF: 0.0000764

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: 0.0000744

Gnomad OTH exome AF: 0.000220

GnomAD4 exome AF: 0.0000609 AC: 86 AN: 1413156 Hom.: 0 Cov.: 31 AF XY: 0.0000655 AC XY: 46 AN XY: 702772

African (AFR) AF: 0.00 AC: 0 AN: 29982

American (AMR) AF: 0.00 AC: 0 AN: 30048

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23870

East Asian (EAS) AF: 0.00 AC: 0 AN: 37674

South Asian (SAS) AF: 0.00 AC: 0 AN: 78298

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5076

European-Non Finnish (NFE) AF: 0.0000774 AC: 85 AN: 1098410

Other (OTH) AF: 0.0000172 AC: 1 AN: 58212

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152164 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74318

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000772 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.0000331 AC: 4

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	Uncertain	0.46
BayesDel_addAF	Uncertain	0.054	T
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.046	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.60	T
M_CAP	Uncertain	0.21	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.5
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.53
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.017	D
Polyphen		0.88	P
Vest4		0.67
MVP		0.85
MPC		0.29
ClinPred		0.25	T
GERP RS		4.6
Varity_R		0.23
gMVP		0.48
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs760510041; hg19: chr7-2580651;