chr14-105211189-G-C

Variant names:

• chr14-105211189-G-C
• rs961802130
• NM_001519.4:c.1929C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001519.4(BRF1):​c.1929C>G​(p.Asp643Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D643D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRF1 NM_001519.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -5.63
• Publications: 0 publications found

Genes affected

BRF1 (HGNC:11551): (BRF1 RNA polymerase III transcription initiation factor subunit) This gene encodes one of the three subunits of the RNA polymerase III transcription factor complex. This complex plays a central role in transcription initiation by RNA polymerase III on genes encoding tRNA, 5S rRNA, and other small structural RNAs. The gene product belongs to the TF2B family. Several alternatively spliced variants encoding different isoforms, that function at different promoters transcribed by RNA polymerase III, have been identified. [provided by RefSeq, Jun 2011]

BRF1 Gene-Disease associations (from GenCC):

• cerebellar-facial-dental syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• colorectal adenoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02732727).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001519.4. 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
	BRF1	NM_001519.4	MANE Select	c.1929C>G	p.Asp643Glu	missense	Exon 17 of 18	NP_001510.2
	BRF1	NM_001440449.1		c.1926C>G	p.Asp642Glu	missense	Exon 17 of 18	NP_001427378.1
	BRF1	NM_001242788.2		c.1848C>G	p.Asp616Glu	missense	Exon 16 of 17	NP_001229717.1	Q92994-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRF1	ENST00000547530.7	TSL:1 MANE Select	c.1929C>G	p.Asp643Glu	missense	Exon 17 of 18	ENSP00000448387.2	Q92994-1
	BRF1	ENST00000379937.6	TSL:1	c.1848C>G	p.Asp616Glu	missense	Exon 16 of 17	ENSP00000369269.2	Q92994-5
	BRF1	ENST00000392557.8	TSL:1	c.1317C>G	p.Asp439Glu	missense	Exon 13 of 14	ENSP00000376340.4	Q92994-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459936 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726294

African (AFR) AF: 0.0000299 AC: 1 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26052

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51868

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111838

Other (OTH) AF: 0.00 AC: 0 AN: 60346

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	0.0010
DANN	Benign	0.25
DEOGEN2	Benign	0.021	T
Eigen	Benign	-2.5
Eigen_PC	Benign	-2.5
FATHMM_MKL	Benign	0.0022	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.17	N
PhyloP100		-5.6
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.046
Sift	Benign	0.61	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.17		Gain of solvent accessibility (P = 0.0638)
MVP		0.10
ClinPred		0.022	T
GERP RS		-8.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.026
gMVP		0.083
Mutation Taster		=86/14	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: rs961802130; hg19: chr14-105677526;