rs606231416

Positions:

• chr14-105241282-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The ENST00000547530.7(BRF1):​c.677C>T​(p.Ser226Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,666 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: BRF1 ENST00000547530.7 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.33

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a repeat 2 (size 84) in uniprot entity TF3B_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in ENST00000547530.7
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867
• PP5: Variant 14-105241282-G-A is Pathogenic according to our data. Variant chr14-105241282-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 161423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRF1	NM_001519.4	c.677C>T	p.Ser226Leu	missense_variant	6/18	ENST00000547530.7	NP_001510.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRF1	ENST00000547530.7	c.677C>T	p.Ser226Leu	missense_variant	6/18	1	NM_001519.4	ENSP00000448387	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000806 AC: 2 AN: 248286 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134962

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000896

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459666 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726150

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.000111 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cerebellar-facial-dental syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	research	Institute of Human Genetics, University of Ulm	Dec 04, 2014	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 05, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 25561519 , 25561519). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.86; 3Cnet: 0.56). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with BRF1-related disorder (ClinVar ID: VCV000161423 / PMID: 25561519). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 25561519). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	.;D;.;D;.;D;.;.;D;D;D
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.6	.;M;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.0	D;.;D;D;D;.;D;D;D;D;D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0020	D;.;D;D;D;.;D;D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;.;.;D
Polyphen		0.98, 0.98	.;D;D;.;.;.;.;.;.;.;.
Vest4		0.91
MutPred		0.67		.;Gain of catalytic residue at C229 (P = 0);.;.;.;.;.;.;.;.;.;
MVP		0.47
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.80
gMVP		0.83

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: rs606231416; hg19: chr14-105707619;