6-31580990-G-T

Position:

• chr6-31580990-G-T

Variant summary

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

The NM_002341.2(LTB):​c.454C>A​(p.Pro152Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000142 in 1,412,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LTB NM_002341.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.131

Genes affected

LTB (HGNC:6711): (lymphotoxin beta) Lymphotoxin beta is a type II membrane protein of the TNF family. It anchors lymphotoxin-alpha to the cell surface through heterotrimer formation. The predominant form on the lymphocyte surface is the lymphotoxin-alpha 1/beta 2 complex (e.g. 1 molecule alpha/2 molecules beta) and this complex is the primary ligand for the lymphotoxin-beta receptor. The minor complex is lymphotoxin-alpha 2/beta 1. LTB is an inducer of the inflammatory response system and involved in normal development of lymphoid tissue. Lymphotoxin-beta isoform b is unable to complex with lymphotoxin-alpha suggesting a function for lymphotoxin-beta which is independent of lympyhotoxin-alpha. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

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=0.12468064).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LTB	NM_002341.2	c.454C>A	p.Pro152Thr	missense_variant	4/4	ENST00000429299.3	NP_002332.1
LTB	NM_009588.1	c.*174C>A		3_prime_UTR_variant	3/3		NP_033666.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LTB	ENST00000429299.3	c.454C>A	p.Pro152Thr	missense_variant	4/4	1	NM_002341.2	ENSP00000410481.3
LTB	ENST00000446745.2	c.*174C>A		3_prime_UTR_variant	3/3	1		ENSP00000416113.2
LTB	ENST00000482429.1	n.1022C>A		non_coding_transcript_exon_variant	2/2	2
LTB	ENST00000483972.1	n.273C>A		non_coding_transcript_exon_variant	3/3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1412048 Hom.: 0 Cov.: 31 AF XY: 0.00000143 AC XY: 1 AN XY: 698260

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: 0.00000184

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Nov 10, 2024

The c.454C>A (p.P152T) alteration is located in exon 4 (coding exon 4) of the LTB gene. This alteration results from a C to A substitution at nucleotide position 454, causing the proline (P) at amino acid position 152 to be replaced by a threonine (T). 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	0.072
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	12
DANN	Benign	0.89
DEOGEN2	Uncertain	0.61	D
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.071	N
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.3	M
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.032
Sift	Benign	0.062	T
Sift4G	Uncertain	0.043	D
Polyphen		0.085	B
Vest4		0.068
MutPred		0.30		Gain of phosphorylation at P152 (P = 0.0349);
MVP		0.41
MPC		1.8
ClinPred		0.11	T
GERP RS		3.3
Varity_R		0.13
gMVP		0.37

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-31548767;