11-57744822-C-A

Variant names:

• chr11-57744822-C-A
• rs1469316551
• NM_001145101.3:c.1451G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001145101.3(BTBD18):​c.1451G>T​(p.Arg484Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BTBD18 NM_001145101.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.97

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]

ENSG00000254732 (HGNC:):

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33245808).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BTBD18	NM_001145101.3	c.1451G>T	p.Arg484Leu	missense_variant	Exon 3 of 3	ENST00000422652.6	NP_001138573.1
BTBD18	XM_017018128.2	c.1451G>T	p.Arg484Leu	missense_variant	Exon 3 of 3		XP_016873617.1
BTBD18	XM_047427405.1	c.1451G>T	p.Arg484Leu	missense_variant	Exon 4 of 4		XP_047283361.1
TMX2-CTNND1	NR_037646.1	n.346+7154C>A		intron_variant	Intron 2 of 20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BTBD18	ENST00000422652.6	c.1451G>T	p.Arg484Leu	missense_variant	Exon 3 of 3	4	NM_001145101.3	ENSP00000394472.1
ENSG00000254732	ENST00000531074.1	n.*152+1838C>A		intron_variant	Intron 2 of 3	3		ENSP00000457993.1
ENSG00000288534	ENST00000674060.1	n.103+7154C>A		intron_variant	Intron 2 of 19			ENSP00000501055.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1451G>T (p.R484L) alteration is located in exon 3 (coding exon 2) of the BTBD18 gene. This alteration results from a G to T substitution at nucleotide position 1451, causing the arginine (R) at amino acid position 484 to be replaced by a leucine (L). 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	0.25
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.039	T;T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.75	.;T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Uncertain	-0.022	T
MutationAssessor	Benign	1.0	L;L
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.45
MutPred		0.35		Loss of solvent accessibility (P = 0.0098);Loss of solvent accessibility (P = 0.0098);
MVP		0.60
ClinPred		0.92	D
GERP RS		5.5
Varity_R		0.29
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1469316551; hg19: chr11-57512294;