15-83056462-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_025238.4(BTBD1):c.485C>T(p.Ala162Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BTBD1 NM_025238.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.81

Genes affected

BTBD1 (HGNC:1120): (BTB domain containing 1) The C-terminus of the protein encoded by this gene binds topoisomerase I. The N-terminus contains a proline-rich region and a BTB/POZ domain (broad-complex, Tramtrack and bric a brac/Pox virus and Zinc finger), both of which are typically involved in protein-protein interactions. Subcellularly, the protein localizes to cytoplasmic bodies. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BTBD1	NM_025238.4	c.485C>T	p.Ala162Val	missense_variant	2/8	ENST00000261721.9
LOC124903542	XR_007064742.1	n.1320-5025G>A		intron_variant, non_coding_transcript_variant
BTBD1	NM_001011885.2	c.485C>T	p.Ala162Val	missense_variant	2/7
BTBD1	XR_007064459.1	n.586C>T		non_coding_transcript_exon_variant	2/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BTBD1	ENST00000261721.9	c.485C>T	p.Ala162Val	missense_variant	2/8	1	NM_025238.4	P1
	ENST00000566841.1	n.735-46962G>A		intron_variant, non_coding_transcript_variant		5
	ENST00000568441.1	n.37+33855G>A		intron_variant, non_coding_transcript_variant		5
	ENST00000570202.1	n.63-5025G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 30, 2024

The c.485C>T (p.A162V) alteration is located in exon 2 (coding exon 2) of the BTBD1 gene. This alteration results from a C to T substitution at nucleotide position 485, causing the alanine (A) at amino acid position 162 to be replaced by a valine (V). 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	Benign	0.28
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D;.
Eigen	Uncertain	0.62
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.65	D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.39
Sift	Benign	0.36	T;T
Sift4G	Benign	0.20	T;D
Polyphen		0.92	P;.
Vest4		0.67
MutPred		0.69		Gain of methylation at K157 (P = 0.1733);Gain of methylation at K157 (P = 0.1733);
MVP		0.85
MPC		1.0
ClinPred		0.99	D
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.69

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: rs1257487844; hg19: chr15-83725214; COSMIC: COSV55601944;