7-2537850-G-T

Variant names:

• chr7-2537850-G-T
• rs145828184
• NM_152743.4:c.*219C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152743.4(BRAT1):​c.*219C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 697,314 control chromosomes in the GnomAD database, including 126 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (18 hom., cov: 33)
  • Exomes 𝑓: 0.012 (108 hom.)
• Consequence: BRAT1 NM_152743.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0160
• 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: 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 7-2537850-G-T is Benign according to our data. Variant chr7-2537850-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 1186082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0574 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAT1	NM_152743.4	c.*219C>A		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.*219C>A		3_prime_UTR_variant	Exon 14 of 14	1	NM_152743.4	ENSP00000339637.4
BRAT1	ENST00000467558.5	n.*31C>A		downstream_gene_variant		5
BRAT1	ENST00000469750.5	n.*31C>A		downstream_gene_variant		2
BRAT1	ENST00000493232.5	n.*31C>A		downstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1935 AN: 152214 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.0197

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.00857

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.0240

Gnomad SAS AF: 0.0360

Gnomad FIN AF: 0.00452

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.00794

Gnomad OTH AF: 0.0158

GnomAD4 exome AF: 0.0120 AC: 6520 AN: 544982 Hom.: 108 Cov.: 8 AF XY: 0.0121 AC XY: 3264 AN XY: 269508

African (AFR) AF: 0.0195 AC: 254 AN: 13002

American (AMR) AF: 0.00798 AC: 89 AN: 11146

Ashkenazi Jewish (ASJ) AF: 0.0146 AC: 179 AN: 12286

East Asian (EAS) AF: 0.0598 AC: 1602 AN: 26790

South Asian (SAS) AF: 0.0321 AC: 578 AN: 18016

European-Finnish (FIN) AF: 0.00363 AC: 90 AN: 24770

Middle Eastern (MID) AF: 0.0311 AC: 63 AN: 2024

European-Non Finnish (NFE) AF: 0.00813 AC: 3324 AN: 409094

Other (OTH) AF: 0.0122 AC: 341 AN: 27854

GnomAD4 genome AF: 0.0127 AC: 1936 AN: 152332 Hom.: 18 Cov.: 33 AF XY: 0.0131 AC XY: 974 AN XY: 74502

African (AFR) AF: 0.0196 AC: 814 AN: 41564

American (AMR) AF: 0.00856 AC: 131 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 47 AN: 3470

East Asian (EAS) AF: 0.0241 AC: 125 AN: 5188

South Asian (SAS) AF: 0.0364 AC: 176 AN: 4834

European-Finnish (FIN) AF: 0.00452 AC: 48 AN: 10618

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.00794 AC: 540 AN: 68036

Other (OTH) AF: 0.0156 AC: 33 AN: 2114

Alfa AF: 0.0101 Hom.: 1

Bravo AF: 0.0128

Asia WGS AF: 0.0180 AC: 62 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 17, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neonatal-onset encephalopathy with rigidity and seizures;C4748032:Neurodevelopmental disorder with cerebellar atrophy and with or without seizures Benign:1

Aug 16, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.70
DANN	Benign	0.42
PhyloP100		-0.016

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs145828184; hg19: chr7-2577484;