chr14-105248982-C-A

Variant names:

• chr14-105248982-C-A
• rs1474209163
• NM_001387567.1:c.271C>A

Variant summary

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

The NM_001387567.1(BTBD6):​c.271C>A​(p.Pro91Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000595 in 840,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. P91S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000059 (0 hom.)
• Consequence: BTBD6 NM_001387567.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.04
• Publications: 0 publications found

Genes affected

BTBD6 (HGNC:19897): (BTB domain containing 6) Predicted to be involved in neurogenesis. Predicted to be located in cytoplasm. Predicted to be active in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

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: 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=0.19161198).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001387567.1. 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
	BTBD6	NM_001387567.1	MANE Select	c.271C>A	p.Pro91Thr	missense	Exon 1 of 4	NP_001374496.1	A0A8C8KHP4
	BRF1	NM_001519.4	MANE Select	c.544+3525G>T		intron	N/A	NP_001510.2
	BTBD6	NM_033271.3		c.112C>A	p.Pro38Thr	missense	Exon 2 of 5	NP_150374.2	Q96KE9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BTBD6	ENST00000392554.8	TSL:1 MANE Select	c.271C>A	p.Pro91Thr	missense	Exon 1 of 4	ENSP00000376337.4	Q96KE9-3
	BRF1	ENST00000547530.7	TSL:1 MANE Select	c.544+3525G>T		intron	N/A	ENSP00000448387.2	Q92994-1
	BRF1	ENST00000379937.6	TSL:1	c.463+3525G>T		intron	N/A	ENSP00000369269.2	Q92994-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000595 AC: 5 AN: 840406 Hom.: 0 Cov.: 30 AF XY: 0.00000257 AC XY: 1 AN XY: 389362

African (AFR) AF: 0.00 AC: 0 AN: 15816

American (AMR) AF: 0.00 AC: 0 AN: 1344

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5352

East Asian (EAS) AF: 0.00 AC: 0 AN: 4006

South Asian (SAS) AF: 0.00 AC: 0 AN: 17318

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1302

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1646

European-Non Finnish (NFE) AF: 0.00000522 AC: 4 AN: 765832

Other (OTH) AF: 0.0000360 AC: 1 AN: 27790

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	15
DANN	Benign	0.91
DEOGEN2	Benign	0.021	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.47	T
M_CAP	Pathogenic	0.61	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.69	N
PhyloP100		3.0
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.087
Sift	Benign	0.43	T
Sift4G	Benign	0.29	T
Polyphen		0.0030	B
Vest4		0.13
MutPred		0.22		Gain of phosphorylation at P38 (P = 0.0046)
MVP		0.54
MPC		0.44
ClinPred		0.089	T
GERP RS		2.6
PromoterAI		0.14	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.6
Varity_R		0.042
gMVP		0.36
Mutation Taster		=93/7	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: rs1474209163; hg19: chr14-105715319;