rs150636332

Variant names:

• chr14-105210578-A-C
• rs150636332
• NM_001519.4:c.2007T>G

Your query was ambiguous. Multiple possible variants found:

• chr14-105210578-A-C
• chr14-105210578-A-G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001519.4(BRF1):​c.2007T>G​(p.Cys669Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C669R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BRF1 NM_001519.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.10
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.102320135).

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.2007T>G	p.Cys669Trp	missense	Exon 18 of 18	NP_001510.2
	BRF1	NM_001440449.1		c.2004T>G	p.Cys668Trp	missense	Exon 18 of 18	NP_001427378.1
	BRF1	NM_001242788.2		c.1926T>G	p.Cys642Trp	missense	Exon 17 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.2007T>G	p.Cys669Trp	missense	Exon 18 of 18	ENSP00000448387.2	Q92994-1
	BRF1	ENST00000379937.6	TSL:1	c.1926T>G	p.Cys642Trp	missense	Exon 17 of 17	ENSP00000369269.2	Q92994-5
	BRF1	ENST00000392557.8	TSL:1	c.1395T>G	p.Cys465Trp	missense	Exon 14 of 14	ENSP00000376340.4	Q92994-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000895 AC: 22 AN: 245904 AF XY: 0.0000673

Gnomad AFR exome AF: 0.00107

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000496

Gnomad NFE exome AF: 0.0000272

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000411 AC: 6 AN: 1459136 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 725840

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

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

European-Finnish (FIN) AF: 0.000118 AC: 6 AN: 50926

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111856

Other (OTH) AF: 0.00 AC: 0 AN: 60336

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000324546), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.000429 AC: 52

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	22
DANN	Benign	0.90
DEOGEN2	Benign	0.067	T
Eigen	Uncertain	0.29
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		3.1
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.29
Sift	Benign	0.085	T
Sift4G	Benign	0.18	T
Polyphen		1.0	D
Vest4		0.57
MVP		0.37
ClinPred		0.080	T
GERP RS		3.4
Varity_R		0.37
gMVP		0.57
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs150636332; hg19: chr14-105676915;