Genetic Variant BTBD18:p.Glu560Gln (chr11-57744595-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_001145101.3(BTBD18):c.1678G>C(p.Glu560Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000786 in 1,399,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 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)

Exomes 𝑓: 0.0000079 ( 0 hom. )

Consequence

BTBD18
NM_001145101.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.79

Variant links:

Genes affected

BTBD18 (HGNC:37214): (BTB domain containing 18) Predicted to be involved in several processes, including male gamete generation; piRNA biosynthetic process; and positive regulation of transcription elongation from RNA polymerase II promoter. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

BTBD18 links:

ENSG00000254732 (HGNC:):

ENSG00000254732 links:

TMX2-CTNND1 (HGNC:41992): (TMX2-CTNND1 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring TMX2 (thioredoxin-related transmembrane protein 2) and CTNND1 (catenin, cadherin-associated protein, delta 1) genes on chromosome 11. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is therefore unlikely to produce a protein product. [provided by RefSeq, Dec 2010]

TMX2-CTNND1 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=0.2139205).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTBD18	NM_001145101.3 link	c.1678G>C	p.Glu560Gln	missense_variant	Exon 3 of 3	ENST00000422652.6	NP_001138573.1	B2RXH4
BTBD18	XM_017018128.2 link	c.1678G>C	p.Glu560Gln	missense_variant	Exon 3 of 3		XP_016873617.1	B2RXH4
BTBD18	XM_047427405.1 link	c.1678G>C	p.Glu560Gln	missense_variant	Exon 4 of 4		XP_047283361.1
TMX2-CTNND1	NR_037646.1 link	n.346+6927C>G		intron_variant	Intron 2 of 20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BTBD18	ENST00000422652.6 link	c.1678G>C	p.Glu560Gln	missense_variant	Exon 3 of 3	4	NM_001145101.3	ENSP00000394472.1	B2RXH4
ENSG00000254732	ENST00000531074.1 link	n.*152+1611C>G		intron_variant	Intron 2 of 3	3		ENSP00000457993.1	H3BV83
ENSG00000288534	ENST00000674060.1 link	n.103+6927C>G		intron_variant	Intron 2 of 19			ENSP00000501055.2	A0A669KB09

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000786

AC:

AN:

1399382

Hom.:

Cov.:

AF XY:

0.00000724

AC XY:

AN XY:

690194

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000102

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 06, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1678G>C (p.E560Q) alteration is located in exon 3 (coding exon 2) of the BTBD18 gene. This alteration results from a G to C substitution at nucleotide position 1678, causing the glutamic acid (E) at amino acid position 560 to be replaced by a glutamine (Q). 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

-0.041

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.018

T;T

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.67

.;T

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.21

T;T

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

1.1

L;L

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.78

N;N

REVEL

Uncertain

0.32

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.031

D;D

Polyphen

0.99

D;D

Vest4

0.12

MutPred

0.067

Gain of helix (P = 0.132);Gain of helix (P = 0.132);

MVP

0.51

ClinPred

0.93

GERP RS

5.5

Varity_R

0.21

gMVP

0.12

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

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