7-2538055-G-A

Variant names:

• chr7-2538055-G-A
• rs140062589
• NM_152743.4:c.*14C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_152743.4(BRAT1):​c.*14C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,528,528 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0064 (14 hom., cov: 33)
  • Exomes 𝑓: 0.00061 (9 hom.)
• Consequence: BRAT1 NM_152743.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0230
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 7-2538055-G-A is Benign according to our data. Variant chr7-2538055-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1199781.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00644 (981/152358) while in subpopulation AFR AF = 0.0225 (936/41584). AF 95% confidence interval is 0.0213. There are 14 homozygotes in GnomAd4. There are 467 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAT1	NM_152743.4	c.*14C>T		3_prime_UTR_variant	Exon 14 of 14	ENST00000340611.9	NP_689956.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRAT1	ENST00000340611.9	c.*14C>T		3_prime_UTR_variant	Exon 14 of 14	1	NM_152743.4	ENSP00000339637.4
BRAT1	ENST00000467558.5	n.4266C>T		non_coding_transcript_exon_variant	Exon 10 of 10	5
BRAT1	ENST00000469750.5	n.5052C>T		non_coding_transcript_exon_variant	Exon 11 of 11	2
BRAT1	ENST00000493232.5	n.5186C>T		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes AF: 0.00642 AC: 978 AN: 152240 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0225

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00222

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: 0.0000882

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00181 AC: 337 AN: 186176 AF XY: 0.00125

Gnomad AFR exome AF: 0.0227

Gnomad AMR exome AF: 0.000649

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000567

Gnomad NFE exome AF: 0.0000459

Gnomad OTH exome AF: 0.000459

GnomAD4 exome AF: 0.000605 AC: 833 AN: 1376170 Hom.: 9 Cov.: 29 AF XY: 0.000524 AC XY: 353 AN XY: 673524

African (AFR) AF: 0.0227 AC: 706 AN: 31104

American (AMR) AF: 0.000821 AC: 28 AN: 34084

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21142

East Asian (EAS) AF: 0.00 AC: 0 AN: 38620

South Asian (SAS) AF: 0.0000685 AC: 5 AN: 72978

European-Finnish (FIN) AF: 0.0000202 AC: 1 AN: 49412

Middle Eastern (MID) AF: 0.000752 AC: 4 AN: 5316

European-Non Finnish (NFE) AF: 0.0000281 AC: 30 AN: 1066780

Other (OTH) AF: 0.00104 AC: 59 AN: 56734

GnomAD4 genome AF: 0.00644 AC: 981 AN: 152358 Hom.: 14 Cov.: 33 AF XY: 0.00627 AC XY: 467 AN XY: 74508

African (AFR) AF: 0.0225 AC: 936 AN: 41584

American (AMR) AF: 0.00222 AC: 34 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68030

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00398 Hom.: 2

Bravo AF: 0.00734

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 15, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.5
DANN	Benign	0.40
PhyloP100		-0.023
Mutation Taster		=100/0	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: rs140062589; hg19: chr7-2577689;