8-37844569-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_018310.4(BRF2):​c.1181G>A​(p.Arg394His) variant causes a missense change. The variant allele was found at a frequency of 0.0000719 in 1,613,874 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

BRF2
NM_018310.4 missense

Scores

5
10
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.60
Variant links:
Genes affected
BRF2 (HGNC:17298): (BRF2 RNA polymerase III transcription initiation factor subunit) This gene encodes one of the multiple subunits of the RNA polymerase III transcription factor complex required for transcription of genes with promoter elements upstream of the initiation site. The product of this gene, a TFIIB-like factor, is directly recruited to the TATA-box of polymerase III small nuclear RNA gene promoters through its interaction with the TATA-binding protein. [provided by RefSeq, Jul 2008]
ADGRA2 (HGNC:17849): (adhesion G protein-coupled receptor A2) Predicted to enable G protein-coupled receptor activity. Involved in positive regulation of canonical Wnt signaling pathway. Part of Wnt signalosome. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.36742473).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BRF2NM_018310.4 linkc.1181G>A p.Arg394His missense_variant Exon 4 of 4 ENST00000220659.11 NP_060780.2 Q9HAW0-1
ADGRA2NM_032777.10 linkc.*2214C>T 3_prime_UTR_variant Exon 19 of 19 ENST00000412232.3 NP_116166.9 Q96PE1-1Q6YN44

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BRF2ENST00000220659.11 linkc.1181G>A p.Arg394His missense_variant Exon 4 of 4 1 NM_018310.4 ENSP00000220659.6 Q9HAW0-1
ADGRA2ENST00000412232.3 linkc.*2214C>T 3_prime_UTR_variant Exon 19 of 19 1 NM_032777.10 ENSP00000406367.2 Q96PE1-1
ADGRA2ENST00000315215.11 linkc.*2214C>T 3_prime_UTR_variant Exon 16 of 16 1 ENSP00000323508.7 Q96PE1-2
BRF2ENST00000520601.5 linkc.*661G>A downstream_gene_variant 3 ENSP00000430107.1 E5RGX1

Frequencies

GnomAD3 genomes
AF:
0.0000592
AC:
9
AN:
152058
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000725
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000197
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000994
AC:
25
AN:
251430
Hom.:
0
AF XY:
0.0000736
AC XY:
10
AN XY:
135910
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000405
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000879
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000732
AC:
107
AN:
1461816
Hom.:
0
Cov.:
31
AF XY:
0.0000660
AC XY:
48
AN XY:
727202
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.000380
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000764
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000592
AC:
9
AN:
152058
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74274
show subpopulations
Gnomad4 AFR
AF:
0.0000725
Gnomad4 AMR
AF:
0.000197
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.0000831
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000824
AC:
10
EpiCase
AF:
0.00
EpiControl
AF:
0.000178

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Aug 07, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1181G>A (p.R394H) alteration is located in exon 4 (coding exon 4) of the BRF2 gene. This alteration results from a G to A substitution at nucleotide position 1181, causing the arginine (R) at amino acid position 394 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.43
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Uncertain
-0.080
CADD
Pathogenic
30
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.42
T
Eigen
Pathogenic
0.73
Eigen_PC
Pathogenic
0.70
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.93
D
M_CAP
Benign
0.010
T
MetaRNN
Benign
0.37
T
MetaSVM
Uncertain
-0.22
T
MutationAssessor
Uncertain
2.6
M
PrimateAI
Uncertain
0.51
T
PROVEAN
Uncertain
-2.8
D
REVEL
Uncertain
0.56
Sift
Uncertain
0.0030
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.31
MVP
0.85
MPC
0.71
ClinPred
0.79
D
GERP RS
5.0
Varity_R
0.74
gMVP
0.76

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs144896527; hg19: chr8-37702087; COSMIC: COSV55105297; COSMIC: COSV55105297; API