14-105249216-C-T

Variant names:

• chr14-105249216-C-T
• rs1187054017
• NM_001387567.1:c.434C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001387567.1(BTBD6):​c.434C>T​(p.Pro145Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,435,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BTBD6 NM_001387567.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.396

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.079921186).
• BP6: Variant 14-105249216-C-T is Benign according to our data. Variant chr14-105249216-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3482806.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTBD6	NM_001387567.1	c.434C>T	p.Pro145Leu	missense_variant	Exon 2 of 4	ENST00000392554.8	NP_001374496.1
BRF1	NM_001519.4	c.544+3291G>A		intron_variant	Intron 5 of 17	ENST00000547530.7	NP_001510.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTBD6	ENST00000392554.8	c.434C>T	p.Pro145Leu	missense_variant	Exon 2 of 4	1	NM_001387567.1	ENSP00000376337.4
BRF1	ENST00000547530.7	c.544+3291G>A		intron_variant	Intron 5 of 17	1	NM_001519.4	ENSP00000448387.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1435406 Hom.: 0 Cov.: 45 AF XY: 0.00000140 AC XY: 1 AN XY: 713310

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: 0.0000237

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000660 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Dec 07, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	12
DANN	Benign	0.93
DEOGEN2	Uncertain	0.51	D;.;D;.;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.016	N
LIST_S2	Uncertain	0.89	D;D;.;.;D
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.080	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.60	N;.;N;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.7	D;D;D;D;D
REVEL	Benign	0.081
Sift	Benign	0.37	T;T;T;T;T
Sift4G	Benign	0.26	T;T;T;T;T
Polyphen		0.0090	B;.;B;.;.
Vest4		0.18
MutPred		0.33		Gain of stability (P = 0.0061);Gain of stability (P = 0.0061);Gain of stability (P = 0.0061);.;.;
MVP		0.30
MPC		0.40
ClinPred		0.026	T
GERP RS		-3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.16

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: rs1187054017; hg19: chr14-105715553;