rs76646873

Variant names:

• chr7-2542142-C-T
• rs76646873
• NM_152743.4:c.993G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-2542142-C-T
• chr7-2542142-C-A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_152743.4(BRAT1):​c.993G>A​(p.Thr331Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00248 in 1,565,760 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (7 hom.)
• Consequence: BRAT1 NM_152743.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.67
• 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, 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 7-2542142-C-T is Benign according to our data. Variant chr7-2542142-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 472985.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.67 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00598 (911/152230) while in subpopulation AFR AF = 0.0158 (655/41536). AF 95% confidence interval is 0.0148. There are 6 homozygotes in GnomAd4. There are 438 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.993G>A	p.Thr331Thr	synonymous	Exon 7 of 14	NP_689956.2	Q6PJG6-1
	BRAT1	NM_001350626.2		c.993G>A	p.Thr331Thr	synonymous	Exon 7 of 14	NP_001337555.1
	BRAT1	NM_001350627.2		c.468G>A	p.Thr156Thr	synonymous	Exon 6 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.993G>A	p.Thr331Thr	synonymous	Exon 7 of 14	ENSP00000339637.4	Q6PJG6-1
	BRAT1	ENST00000890463.1		c.993G>A	p.Thr331Thr	synonymous	Exon 7 of 16	ENSP00000560522.1
	BRAT1	ENST00000917322.1		c.990G>A	p.Thr330Thr	synonymous	Exon 7 of 16	ENSP00000587381.1

Frequencies

GnomAD3 genomes AF: 0.00601 AC: 914 AN: 152112 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0158

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00574

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00231

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00246 AC: 438 AN: 178246 AF XY: 0.00222

Gnomad AFR exome AF: 0.0125

Gnomad AMR exome AF: 0.000716

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00775

Gnomad NFE exome AF: 0.00201

Gnomad OTH exome AF: 0.00107

GnomAD4 exome AF: 0.00211 AC: 2978 AN: 1413530 Hom.: 7 Cov.: 32 AF XY: 0.00204 AC XY: 1428 AN XY: 699174

African (AFR) AF: 0.0150 AC: 484 AN: 32290

American (AMR) AF: 0.00102 AC: 38 AN: 37430

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24872

East Asian (EAS) AF: 0.00 AC: 0 AN: 37422

South Asian (SAS) AF: 0.0000500 AC: 4 AN: 80080

European-Finnish (FIN) AF: 0.00615 AC: 304 AN: 49470

Middle Eastern (MID) AF: 0.000355 AC: 2 AN: 5638

European-Non Finnish (NFE) AF: 0.00185 AC: 2008 AN: 1087870

Other (OTH) AF: 0.00236 AC: 138 AN: 58458

GnomAD4 genome AF: 0.00598 AC: 911 AN: 152230 Hom.: 6 Cov.: 32 AF XY: 0.00589 AC XY: 438 AN XY: 74416

African (AFR) AF: 0.0158 AC: 655 AN: 41536

American (AMR) AF: 0.00209 AC: 32 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00574 AC: 61 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00231 AC: 157 AN: 68000

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00388 Hom.: 3

Bravo AF: 0.00587

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Neonatal-onset encephalopathy with rigidity and seizures (1)
-	-	1	Neonatal-onset encephalopathy with rigidity and seizures;C4748032:Neurodevelopmental disorder with cerebellar atrophy and with or without seizures (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.20
DANN	Benign	0.48
PhyloP100		-3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs76646873; hg19: chr7-2581776;