chr8-37844696-C-A

Position:

• chr8-37844696-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018310.4(BRF2):​c.1054G>T​(p.Ala352Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRF2 NM_018310.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.00500

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04331416).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRF2	NM_018310.4	c.1054G>T	p.Ala352Ser	missense_variant	4/4	ENST00000220659.11	NP_060780.2
ADGRA2	NM_032777.10	c.*2341C>A		3_prime_UTR_variant	19/19	ENST00000412232.3	NP_116166.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRF2	ENST00000220659.11	c.1054G>T	p.Ala352Ser	missense_variant	4/4	1	NM_018310.4	ENSP00000220659.6
ADGRA2	ENST00000412232.3	c.*2341C>A		3_prime_UTR_variant	19/19	1	NM_032777.10	ENSP00000406367.2
ADGRA2	ENST00000315215.11	c.*2341C>A		3_prime_UTR_variant	16/16	1		ENSP00000323508.7
BRF2	ENST00000520601.5	c.*534G>T		downstream_gene_variant		3		ENSP00000430107.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461806 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727196

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2021

The c.1054G>T (p.A352S) alteration is located in exon 4 (coding exon 4) of the BRF2 gene. This alteration results from a G to T substitution at nucleotide position 1054, causing the alanine (A) at amino acid position 352 to be replaced by a serine (S). 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	Benign	0.086
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	5.1
DANN	Benign	0.95
DEOGEN2	Benign	0.013	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.31	N
REVEL	Benign	0.080
Sift	Benign	0.23	T
Sift4G	Benign	0.36	T
Polyphen		0.0	B
Vest4		0.064
MutPred		0.18		Gain of phosphorylation at A352 (P = 0.009);
MVP		0.23
MPC		0.13
ClinPred		0.18	T
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.068
gMVP		0.18

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

Other links and lift over

dbSNP: rs868725875; hg19: chr8-37702214;