15-83067085-C-G

Position:

• chr15-83067085-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_025238.4(BTBD1):​c.67G>C​(p.Ala23Pro) 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. 14/21 in silico tools predict a benign outcome for this variant. 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: -0.365

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13825789).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BTBD1	NM_025238.4	c.67G>C	p.Ala23Pro	missense_variant	1/8	ENST00000261721.9
BTBD1	NM_001011885.2	c.67G>C	p.Ala23Pro	missense_variant	1/7
BTBD1	XR_007064459.1	n.168G>C		non_coding_transcript_exon_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BTBD1	ENST00000261721.9	c.67G>C	p.Ala23Pro	missense_variant	1/8	1	NM_025238.4	P1
	ENST00000566841.1	n.735-36339C>G		intron_variant, non_coding_transcript_variant		5
	ENST00000568441.1	n.38-23236C>G		intron_variant, non_coding_transcript_variant		5
BTBD1	ENST00000379403.2	c.67G>C	p.Ala23Pro	missense_variant	1/7	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.0000113

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

Jul 06, 2021

The c.67G>C (p.A23P) alteration is located in exon 1 (coding exon 1) of the BTBD1 gene. This alteration results from a G to C substitution at nucleotide position 67, causing the alanine (A) at amino acid position 23 to be replaced by a proline (P). 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	0.065
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	12
DANN	Benign	0.91
DEOGEN2	Benign	0.025	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0083	N
LIST_S2	Benign	0.50	T;T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.46	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.83	N;N
REVEL	Benign	0.15
Sift	Benign	0.33	T;T
Sift4G	Benign	0.34	T;T
Polyphen		0.15	B;.
Vest4		0.089
MutPred		0.25		Gain of glycosylation at A23 (P = 0.0019);Gain of glycosylation at A23 (P = 0.0019);
MVP		0.55
MPC		0.61
ClinPred		0.33	T
GERP RS		-3.9
Varity_R		0.17
gMVP		0.46

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: rs2033295852; hg19: chr15-83735837;