7-2538673-C-T

Variant names:

• chr7-2538673-C-T
• rs138077616
• NM_152743.4:c.1862G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_152743.4(BRAT1):​c.1862G>A​(p.Arg621Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 1,598,336 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R621P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0025 (18 hom.)
• Consequence: BRAT1 NM_152743.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0450
• 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, 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004225254).
• BP6: Variant 7-2538673-C-T is Benign according to our data. Variant chr7-2538673-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 540188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 18 AR gene

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.1862G>A	p.Arg621Gln	missense	Exon 14 of 14	NP_689956.2	Q6PJG6-1
	BRAT1	NM_001350626.2		c.2042G>A	p.Arg681Gln	missense	Exon 14 of 14	NP_001337555.1
	BRAT1	NM_001350627.2		c.1337G>A	p.Arg446Gln	missense	Exon 13 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.1862G>A	p.Arg621Gln	missense	Exon 14 of 14	ENSP00000339637.4	Q6PJG6-1
	BRAT1	ENST00000890463.1		c.2099G>A	p.Arg700Gln	missense	Exon 16 of 16	ENSP00000560522.1
	BRAT1	ENST00000917322.1		c.2096G>A	p.Arg699Gln	missense	Exon 16 of 16	ENSP00000587381.1

Frequencies

GnomAD3 genomes AF: 0.00185 AC: 282 AN: 152188 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000981

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00269

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00205 AC: 472 AN: 229856 AF XY: 0.00232

Gnomad AFR exome AF: 0.000350

Gnomad AMR exome AF: 0.000846

Gnomad ASJ exome AF: 0.00133

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00254

Gnomad NFE exome AF: 0.00207

Gnomad OTH exome AF: 0.00257

GnomAD4 exome AF: 0.00247 AC: 3573 AN: 1446030 Hom.: 18 Cov.: 70 AF XY: 0.00263 AC XY: 1894 AN XY: 719808

African (AFR) AF: 0.000239 AC: 8 AN: 33472

American (AMR) AF: 0.000760 AC: 34 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.000957 AC: 25 AN: 26126

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39686

South Asian (SAS) AF: 0.00561 AC: 484 AN: 86244

European-Finnish (FIN) AF: 0.00253 AC: 96 AN: 38014

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5766

European-Non Finnish (NFE) AF: 0.00252 AC: 2802 AN: 1111748

Other (OTH) AF: 0.00186 AC: 112 AN: 60260

GnomAD4 genome AF: 0.00185 AC: 282 AN: 152306 Hom.: 0 Cov.: 34 AF XY: 0.00191 AC XY: 142 AN XY: 74478

African (AFR) AF: 0.000457 AC: 19 AN: 41568

American (AMR) AF: 0.000980 AC: 15 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00414 AC: 20 AN: 4830

European-Finnish (FIN) AF: 0.00358 AC: 38 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00269 AC: 183 AN: 68018

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00188 Hom.: 1

Bravo AF: 0.00149

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000461 AC: 2

ESP6500EA AF: 0.00201 AC: 17

ExAC AF: 0.00207 AC: 248

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00191

EpiControl AF: 0.00154

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	BRAT1-related disorder (1)
-	-	1	Neonatal-onset encephalopathy with rigidity and seizures (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0058	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.045
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.076
Sift	Benign	0.20	T
Sift4G	Benign	0.14	T
Polyphen		0.74	P
Vest4		0.12
MVP		0.57
MPC		0.064
ClinPred		0.0066	T
GERP RS		3.4
Varity_R		0.077
gMVP		0.18
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs138077616; hg19: chr7-2578307;