chr7-2541360-G-C

Variant names:

• chr7-2541360-G-C
• rs779635361
• NM_152743.4:c.1259C>G

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.1259C>G​(p.Ala420Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000249 in 1,606,984 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A420V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BRAT1 NM_152743.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.343
• 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, Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• 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=0.06713703).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAT1	NM_152743.4	c.1259C>G	p.Ala420Gly	missense_variant	Exon 9 of 14	ENST00000340611.9	NP_689956.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAT1	ENST00000340611.9	c.1259C>G	p.Ala420Gly	missense_variant	Exon 9 of 14	1	NM_152743.4	ENSP00000339637.4
BRAT1	ENST00000467558.5	n.1541C>G		non_coding_transcript_exon_variant	Exon 7 of 10	5
BRAT1	ENST00000469750.5	n.2741C>G		non_coding_transcript_exon_variant	Exon 7 of 11	2
BRAT1	ENST00000493232.5	n.2660C>G		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000844 AC: 2 AN: 237038 AF XY: 0.00000766

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000112

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1454704 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 723880

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44538

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 86094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111504

Other (OTH) AF: 0.00 AC: 0 AN: 60246

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74460

African (AFR) AF: 0.00 AC: 0 AN: 41560

American (AMR) AF: 0.00 AC: 0 AN: 15300

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

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68002

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

Alfa AF: 0.00 Hom.: 0

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	11
DANN	Benign	0.95
DEOGEN2	Benign	0.0037	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.98	L
PhyloP100		0.34
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.073
Sift	Benign	0.076	T
Sift4G	Benign	0.098	T
Polyphen		0.0010	B
Vest4		0.17
MutPred		0.36		Loss of helix (P = 0.0237);
MVP		0.28
MPC		0.047
ClinPred		0.025	T
GERP RS		-3.6
Varity_R		0.055
gMVP		0.24
Mutation Taster		=97/3	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: rs779635361; hg19: chr7-2580994;