14-105248877-G-A

Variant names:

• chr14-105248877-G-A
• rs973481427
• NM_001387567.1:c.166G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001387567.1(BTBD6):​c.166G>A​(p.Ala56Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000342 in 146,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000034 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: BTBD6 NM_001387567.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.54
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32682183).

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.166G>A	p.Ala56Thr	missense	Exon 1 of 4	NP_001374496.1	A0A8C8KHP4
	BRF1	NM_001519.4	MANE Select	c.544+3630C>T		intron	N/A	NP_001510.2
	BTBD6	NM_033271.3		c.7G>A	p.Ala3Thr	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.166G>A	p.Ala56Thr	missense	Exon 1 of 4	ENSP00000376337.4	Q96KE9-3
	BRF1	ENST00000547530.7	TSL:1 MANE Select	c.544+3630C>T		intron	N/A	ENSP00000448387.2	Q92994-1
	BRF1	ENST00000379937.6	TSL:1	c.463+3630C>T		intron	N/A	ENSP00000369269.2	Q92994-5

Frequencies

GnomAD3 genomes AF: 0.0000342 AC: 5 AN: 146052 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 842664 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 389966

African (AFR) AF: 0.00 AC: 0 AN: 15936

American (AMR) AF: 0.00 AC: 0 AN: 1260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5398

East Asian (EAS) AF: 0.00 AC: 0 AN: 4032

South Asian (SAS) AF: 0.00 AC: 0 AN: 17276

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1660

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 767976

Other (OTH) AF: 0.00 AC: 0 AN: 27838

GnomAD4 genome AF: 0.0000342 AC: 5 AN: 146052 Hom.: 0 Cov.: 31 AF XY: 0.0000422 AC XY: 3 AN XY: 71010

African (AFR) AF: 0.000123 AC: 5 AN: 40574

American (AMR) AF: 0.00 AC: 0 AN: 14756

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3394

East Asian (EAS) AF: 0.00 AC: 0 AN: 5008

South Asian (SAS) AF: 0.00 AC: 0 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8522

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 302

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65772

Other (OTH) AF: 0.00 AC: 0 AN: 2024

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.060	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.81	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.5
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.92	N
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.024	D
Polyphen		0.52	P
Vest4		0.36
MutPred		0.17		Loss of helix (P = 0.0093)
MVP		0.77
MPC		0.38
ClinPred		0.77	D
GERP RS		2.4
PromoterAI		-0.30	Neutral
Varity_R		0.19
gMVP		0.72
Mutation Taster		=85/15	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: rs973481427; hg19: chr14-105715214;