NM_000595.4:c.511G>A

Variant names:

• chr6-31573586-G-A
• NM_000595.4:c.511G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 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
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000595.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTA	NM_000595.4	MANE Select	c.511G>A	p.Ala171Thr	missense	Exon 4 of 4	NP_000586.2
	LTA	NM_001159740.2		c.511G>A	p.Ala171Thr	missense	Exon 4 of 4	NP_001153212.1	Q5STV3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTA	ENST00000418386.3	TSL:1 MANE Select	c.511G>A	p.Ala171Thr	missense	Exon 4 of 4	ENSP00000413450.2	P01374
	LTA	ENST00000454783.5	TSL:2	c.511G>A	p.Ala171Thr	missense	Exon 4 of 4	ENSP00000403495.1	P01374
	LTA	ENST00000877327.1		c.511G>A	p.Ala171Thr	missense	Exon 3 of 3	ENSP00000547386.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		3.7
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.90		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
Mutation Taster		=53/47	polymorphism

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

Other links and lift over

hg19: chr6-31541363;