chr7-2538108-C-G

Variant names:

• chr7-2538108-C-G
• rs760489828
• NM_152743.4:c.2427G>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_152743.4(BRAT1):​c.2427G>C​(p.Thr809Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000101 in 1,591,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. T809T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000097 (0 hom.)
• Consequence: BRAT1 NM_152743.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.97
• Publications: 0 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: Orphanet, Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, ClinGen
• 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 -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 7-2538108-C-G is Benign according to our data. Variant chr7-2538108-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1134839.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.97 with no splicing effect.

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.2427G>C	p.Thr809Thr	synonymous	Exon 14 of 14	NP_689956.2	Q6PJG6-1
	BRAT1	NM_001350626.2		c.2607G>C	p.Thr869Thr	synonymous	Exon 14 of 14	NP_001337555.1
	BRAT1	NM_001350627.2		c.1902G>C	p.Thr634Thr	synonymous	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.2427G>C	p.Thr809Thr	synonymous	Exon 14 of 14	ENSP00000339637.4	Q6PJG6-1
	BRAT1	ENST00000890463.1		c.2664G>C	p.Thr888Thr	synonymous	Exon 16 of 16	ENSP00000560522.1
	BRAT1	ENST00000917322.1		c.2661G>C	p.Thr887Thr	synonymous	Exon 16 of 16	ENSP00000587381.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000169 AC: 4 AN: 236864 AF XY: 0.0000154

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000378

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000973 AC: 14 AN: 1438976 Hom.: 0 Cov.: 31 AF XY: 0.00000843 AC XY: 6 AN XY: 711754

African (AFR) AF: 0.00 AC: 0 AN: 32976

American (AMR) AF: 0.00 AC: 0 AN: 43518

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25442

East Asian (EAS) AF: 0.00 AC: 0 AN: 39168

South Asian (SAS) AF: 0.00 AC: 0 AN: 84904

European-Finnish (FIN) AF: 0.0000386 AC: 2 AN: 51868

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.0000100 AC: 11 AN: 1096128

Other (OTH) AF: 0.0000169 AC: 1 AN: 59270

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152228 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74376

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Neonatal-onset encephalopathy with rigidity and seizures (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.0030
DANN	Benign	0.42
PhyloP100		-2.0

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: rs760489828; hg19: chr7-2577742;