NM_152743.4:c.1925C>G

Variant names:

• chr7-2538610-G-C
• rs200502048
• NM_152743.4:c.1925C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM2 PM5 BP4_Strong

The NM_152743.4(BRAT1):​c.1925C>G​(p.Ala642Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 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. A642E) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.00017 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BRAT1 NM_152743.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.868
• Publications: 9 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-2538610-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 449963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.02861756).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRAT1	NM_152743.4	c.1925C>G	p.Ala642Gly	missense_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.1925C>G	p.Ala642Gly	missense_variant	Exon 14 of 14	1	NM_152743.4	ENSP00000339637.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00150 AC: 308 AN: 205230 AF XY: 0.00161

Gnomad AFR exome AF: 0.00155

Gnomad AMR exome AF: 0.00266

Gnomad ASJ exome AF: 0.000328

Gnomad EAS exome AF: 0.00106

Gnomad FIN exome AF: 0.000991

Gnomad NFE exome AF: 0.00181

Gnomad OTH exome AF: 0.000564

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000172 AC: 246 AN: 1432984 Hom.: 0 Cov.: 66 AF XY: 0.000185 AC XY: 132 AN XY: 712540

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000242 AC: 8 AN: 33022

American (AMR) AF: 0.00227 AC: 95 AN: 41930

Ashkenazi Jewish (ASJ) AF: 0.000117 AC: 3 AN: 25730

East Asian (EAS) AF: 0.000909 AC: 35 AN: 38488

South Asian (SAS) AF: 0.000118 AC: 10 AN: 84962

European-Finnish (FIN) AF: 0.000319 AC: 12 AN: 37652

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5668

European-Non Finnish (NFE) AF: 0.0000696 AC: 77 AN: 1105864

Other (OTH) AF: 0.0000838 AC: 5 AN: 59668

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ExAC AF: 0.00207 AC: 245

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	11
DANN	Benign	0.68
DEOGEN2	Benign	0.0066	T
Eigen	Benign	-0.90
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.71	T
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.87
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.20
Sift	Benign	0.53	T
Sift4G	Benign	0.71	T
Polyphen		0.95	P
Vest4		0.23
MVP		0.29
MPC		0.048
ClinPred		0.016	T
GERP RS		0.31
Varity_R		0.045
gMVP		0.31
Mutation Taster		=69/31	polymorphism

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: rs200502048; hg19: chr7-2578244;