6-31573586-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000595.4(LTA):c.511G>A(p.Ala171Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: LTA NM_000595.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.73

Genes affected

LTA (HGNC:6709): (lymphotoxin alpha) The encoded protein, a member of the tumor necrosis factor family, is a cytokine produced by lymphocytes. The protein is highly inducible, secreted, and forms heterotrimers with lymphotoxin-beta which anchor lymphotoxin-alpha to the cell surface. This protein also mediates a large variety of inflammatory, immunostimulatory, and antiviral responses, is involved in the formation of secondary lymphoid organs during development and plays a role in apoptosis. Genetic variations in this gene are associated with susceptibility to leprosy type 4, myocardial infarction, non-Hodgkin's lymphoma, and psoriatic arthritis. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Jul 2012]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LTA	NM_000595.4	c.511G>A	p.Ala171Thr	missense_variant	4/4	ENST00000418386.3
LTA	NM_001159740.2	c.511G>A	p.Ala171Thr	missense_variant	4/4
LTA	XM_047418773.1	c.511G>A	p.Ala171Thr	missense_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LTA	ENST00000418386.3	c.511G>A	p.Ala171Thr	missense_variant	4/4	1	NM_000595.4	P1
LTA	ENST00000454783.5	c.511G>A	p.Ala171Thr	missense_variant	4/4	2		P1
LTA	ENST00000471842.1	n.759G>A		non_coding_transcript_exon_variant	3/3	2
LTA	ENST00000489638.5	n.639G>A		non_coding_transcript_exon_variant	3/3	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

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

Aug 28, 2023

The c.511G>A (p.A171T) alteration is located in exon 4 (coding exon 3) of the LTA gene. This alteration results from a G to A substitution at nucleotide position 511, causing the alanine (A) at amino acid position 171 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	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D;D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Pathogenic	3.2	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.69
MutPred		0.90		Loss of catalytic residue at A171 (P = 0.1312);Loss of catalytic residue at A171 (P = 0.1312);
MVP		0.88
MPC		2.0
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.76
gMVP		0.93

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: chr6-31541363;