14-105226674-G-A

Variant names:

• chr14-105226674-G-A
• rs606231450
• NM_001519.4:c.875C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_001519.4(BRF1):​c.875C>T​(p.Pro292Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P292H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: BRF1 NM_001519.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.38
• 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: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• colorectal adenoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr14-105226674-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 161426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908

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.875C>T	p.Pro292Leu	missense	Exon 8 of 18	NP_001510.2
	BRF1	NM_001440449.1		c.875C>T	p.Pro292Leu	missense	Exon 8 of 18	NP_001427378.1
	BRF1	NM_001242788.2		c.794C>T	p.Pro265Leu	missense	Exon 7 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.875C>T	p.Pro292Leu	missense	Exon 8 of 18	ENSP00000448387.2	Q92994-1
	BRF1	ENST00000379937.6	TSL:1	c.794C>T	p.Pro265Leu	missense	Exon 7 of 17	ENSP00000369269.2	Q92994-5
	BRF1	ENST00000392557.8	TSL:1	c.263C>T	p.Pro88Leu	missense	Exon 4 of 14	ENSP00000376340.4	Q92994-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461222 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726896

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52778

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111998

Other (OTH) AF: 0.0000331 AC: 2 AN: 60384

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

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	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.4
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-9.1	D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.021	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.40		Gain of catalytic residue at A296 (P = 0.0021)
MVP		0.64
ClinPred		1.0	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.82
gMVP		0.79
Mutation Taster		=8/92	disease causing

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: rs606231450; hg19: chr14-105693011;