Genetic Variant NM_001519.4:c.875C>T (chr14-105226674-G-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3_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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.38

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 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 Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.908

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRF1	NM_001519.4 link	c.875C>T	p.Pro292Leu	missense_variant	Exon 8 of 18	ENST00000547530.7	NP_001510.2	Q92994-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRF1	ENST00000547530.7 link	c.875C>T	p.Pro292Leu	missense_variant	Exon 8 of 18	1	NM_001519.4	ENSP00000448387.2		Q92994-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461222

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726896

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000270

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Mar 22, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.875C>T (p.P292L) alteration is located in exon 8 (coding exon 8) of the BRF1 gene. This alteration results from a C to T substitution at nucleotide position 875, causing the proline (P) at amino acid position 292 to be replaced by a leucine (L). The p.P292L alteration is predicted to be deleterious by in silico analysis. 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

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.59

.;D;.;.;D;.;D;.;.;D;D

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.63

MetaRNN

Pathogenic

0.91

D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.33

MutationAssessor

Uncertain

2.8

.;M;.;.;.;.;.;.;.;.;.

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-9.1

D;.;D;D;D;D;.;D;D;D;D

REVEL

Pathogenic

0.71

Sift

Pathogenic

0.0

D;.;D;D;D;D;.;D;D;D;D

Sift4G

Uncertain

0.021

D;D;D;D;D;T;D;D;D;.;.

Polyphen

1.0

.;D;D;.;.;.;.;.;.;.;.

Vest4

0.96

MutPred

0.40

.;Gain of catalytic residue at A296 (P = 0.0021);.;.;.;.;.;.;.;.;.;

MVP

0.64

ClinPred

1.0

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.7

Varity_R

0.82

gMVP

0.79

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over