7-2543714-G-C

Variant names:

• chr7-2543714-G-C
• rs79263074
• NM_152743.4:c.679C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152743.4(BRAT1):​c.679C>G​(p.Arg227Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R227C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BRAT1 NM_152743.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.89
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24433336).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAT1	NM_152743.4	MANE Select	c.679C>G	p.Arg227Gly	missense	Exon 5 of 14	NP_689956.2
	BRAT1	NM_001350626.2		c.679C>G	p.Arg227Gly	missense	Exon 5 of 14	NP_001337555.1
	BRAT1	NM_001350627.2		c.154C>G	p.Arg52Gly	missense	Exon 4 of 13	NP_001337556.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRAT1	ENST00000340611.9	TSL:1 MANE Select	c.679C>G	p.Arg227Gly	missense	Exon 5 of 14	ENSP00000339637.4
	BRAT1	ENST00000421712.1	TSL:3	n.*24C>G		non_coding_transcript_exon	Exon 3 of 5	ENSP00000409209.2
	BRAT1	ENST00000467558.5	TSL:5	n.695C>G		non_coding_transcript_exon	Exon 4 of 10

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1430168 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 706140

African (AFR) AF: 0.00 AC: 0 AN: 32960

American (AMR) AF: 0.00 AC: 0 AN: 43150

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24786

East Asian (EAS) AF: 0.00 AC: 0 AN: 38986

South Asian (SAS) AF: 0.00 AC: 0 AN: 83514

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51792

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5648

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1090468

Other (OTH) AF: 0.00 AC: 0 AN: 58864

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152214 Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1 AN XY: 74362

African (AFR) AF: 0.0000241 AC: 1 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

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: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 2

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0027	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.19
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.9
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.42
Sift	Benign	0.25	T
Sift4G	Benign	0.41	T
Polyphen		0.83	P
Vest4		0.29
MutPred		0.37		Gain of helix (P = 0.0696)
MVP		0.89
MPC		0.056
ClinPred		0.31	T
GERP RS		4.8
Varity_R		0.080
gMVP		0.10
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs79263074; hg19: chr7-2583348;