12-6384410-G-A

Variant summary

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

The NM_002342.3(LTBR):c.52G>A(p.Val18Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,391,370 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LTBR NM_002342.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.834

Genes affected

LTBR (HGNC:6718): (lymphotoxin beta receptor) This gene encodes a member of the tumor necrosis factor receptor superfamily. The major ligands of this receptor include lymphotoxin alpha/beta and tumor necrosis factor ligand superfamily member 14. The encoded protein plays a role in signalling during the development of lymphoid and other organs, lipid metabolism, immune response, and programmed cell death. Activity of this receptor has also been linked to carcinogenesis. Alternatively spliced transcript variants encoding multiple isoforms have been observed. [provided by RefSeq, Aug 2012]

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=0.072882265).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LTBR	NM_002342.3	c.52G>A	p.Val18Met	missense_variant	1/10	ENST00000228918.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LTBR	ENST00000228918.9	c.52G>A	p.Val18Met	missense_variant	1/10	1	NM_002342.3	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000142 AC: 2 AN: 140962 Hom.: 0 AF XY: 0.0000131 AC XY: 1 AN XY: 76430

Gnomad AFR exome AF: 0.000276

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1391370 Hom.: 0 Cov.: 33 AF XY: 0.00000146 AC XY: 1 AN XY: 686994

Gnomad4 AFR exome AF: 0.0000628

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

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 04, 2024

The c.52G>A (p.V18M) alteration is located in exon 1 (coding exon 1) of the LTBR gene. This alteration results from a G to A substitution at nucleotide position 52, causing the valine (V) at amino acid position 18 to be replaced by a methionine (M). 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	0.22
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	6.8
Dann	Benign	0.93
DEOGEN2	Benign	0.13	T;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0093	N
LIST_S2	Benign	0.63	T;T
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.073	T;T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.90	L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	0.21	N;N
REVEL	Benign	0.23
Sift	Benign	0.17	T;T
Sift4G	Benign	0.43	T;T
Polyphen		0.062	B;.
Vest4		0.13
MutPred		0.39		Loss of catalytic residue at V18 (P = 0.1053);Loss of catalytic residue at V18 (P = 0.1053);
MVP		0.58
MPC		0.96
ClinPred		0.012	T
GERP RS		-4.2
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.8
Varity_R		0.029
gMVP		0.52

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: rs1331026150; hg19: chr12-6493576;