Genetic Variant BTBD8:p.Thr275Ser (chr1-92139421-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001376131.1(BTBD8):c.824C>G(p.Thr275Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

BTBD8
NM_001376131.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.20

Variant links:

Genes affected

BTBD8 (HGNC:21019): (BTB domain containing 8) Predicted to be involved in clathrin-dependent synaptic vesicle endocytosis; neuron projection development; and synaptic vesicle budding from endosome. Located in nucleoplasm. Colocalizes with AP-2 adaptor complex. [provided by Alliance of Genome Resources, Apr 2022]

BTBD8 links:

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ACMG classification

Classification made for transcript

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=0.18828091).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTBD8	NM_001376131.1 link	c.824C>G	p.Thr275Ser	missense_variant	Exon 6 of 18	ENST00000636805.2	NP_001363060.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTBD8	ENST00000636805.2 link	c.824C>G	p.Thr275Ser	missense_variant	Exon 6 of 18	5	NM_001376131.1	ENSP00000490161.1		Q5XKL5-3

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152084

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.824C>G (p.T275S) alteration is located in exon 6 (coding exon 6) of the BTBD8 gene. This alteration results from a C to G substitution at nucleotide position 824, causing the threonine (T) at amino acid position 275 to be replaced by a serine (S). 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

0.11

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.081

.;T

Eigen

Benign

-0.20

Eigen_PC

Benign

0.012

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.56

T;T

M_CAP

Benign

0.010

MetaRNN

Benign

0.19

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.11

.;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.0

.;N

REVEL

Benign

0.082

Sift

Benign

0.085

.;T

Sift4G

Uncertain

0.046

.;D

Polyphen

0.0030

.;B

Vest4

0.17

MutPred

0.40

Gain of disorder (P = 0.0529);Gain of disorder (P = 0.0529);

MVP

0.88

MPC

0.19

ClinPred

0.39

GERP RS

4.3

Varity_R

0.087

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over