6-31573007-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000595.4(LTA):c.179C>A(p.Thr60Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 1,611,200 control chromosomes in the GnomAD database, including 103,451 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T60A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.38 (11465 hom., cov: 28)
  • Exomes 𝑓: 0.35 (91986 hom.)
• Consequence: LTA NM_000595.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 0.741

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.4083595E-4).
• BP6: Variant 6-31573007-C-A is Benign according to our data. Variant chr6-31573007-C-A is described in ClinVar as [Benign]. Clinvar id is 14379.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LTA	NM_000595.4	c.179C>A	p.Thr60Asn	missense_variant	3/4	ENST00000418386.3
LTA	NM_001159740.2	c.179C>A	p.Thr60Asn	missense_variant	3/4
LTA	XM_047418773.1	c.179C>A	p.Thr60Asn	missense_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LTA	ENST00000418386.3	c.179C>A	p.Thr60Asn	missense_variant	3/4	1	NM_000595.4	P1
LTA	ENST00000454783.5	c.179C>A	p.Thr60Asn	missense_variant	3/4	2		P1
LTA	ENST00000471842.1	n.427C>A		non_coding_transcript_exon_variant	2/3	2
LTA	ENST00000489638.5	n.307C>A		non_coding_transcript_exon_variant	2/3	5

Frequencies

GnomAD3 genomes AF: 0.381 AC: 57634 AN: 151122 Hom.: 11454 Cov.: 28

Gnomad AFR AF: 0.502

Gnomad AMI AF: 0.366

Gnomad AMR AF: 0.346

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.471

Gnomad SAS AF: 0.277

Gnomad FIN AF: 0.298

Gnomad MID AF: 0.341

Gnomad NFE AF: 0.339

Gnomad OTH AF: 0.350

GnomAD3 exomes AF: 0.347 AC: 85595 AN: 246840 Hom.: 15475 AF XY: 0.339 AC XY: 45608 AN XY: 134378

Gnomad AFR exome AF: 0.501

Gnomad AMR exome AF: 0.338

Gnomad ASJ exome AF: 0.241

Gnomad EAS exome AF: 0.498

Gnomad SAS exome AF: 0.288

Gnomad FIN exome AF: 0.300

Gnomad NFE exome AF: 0.338

Gnomad OTH exome AF: 0.331

GnomAD4 exome AF: 0.351 AC: 512722 AN: 1459960 Hom.: 91986 Cov.: 44 AF XY: 0.348 AC XY: 252459 AN XY: 726340

Gnomad4 AFR exome AF: 0.508

Gnomad4 AMR exome AF: 0.336

Gnomad4 ASJ exome AF: 0.250

Gnomad4 EAS exome AF: 0.434

Gnomad4 SAS exome AF: 0.284

Gnomad4 FIN exome AF: 0.313

Gnomad4 NFE exome AF: 0.353

Gnomad4 OTH exome AF: 0.352

GnomAD4 genome AF: 0.381 AC: 57687 AN: 151240 Hom.: 11465 Cov.: 28 AF XY: 0.377 AC XY: 27836 AN XY: 73858

Gnomad4 AFR AF: 0.502

Gnomad4 AMR AF: 0.346

Gnomad4 ASJ AF: 0.241

Gnomad4 EAS AF: 0.471

Gnomad4 SAS AF: 0.277

Gnomad4 FIN AF: 0.298

Gnomad4 NFE AF: 0.339

Gnomad4 OTH AF: 0.348

Alfa AF: 0.337 Hom.: 19942

Bravo AF: 0.391

TwinsUK AF: 0.375 AC: 1391

ALSPAC AF: 0.379 AC: 1459

ESP6500AA AF: 0.511 AC: 1543

ESP6500EA AF: 0.331 AC: 1793

ExAC AF: 0.347 AC: 41204

Asia WGS AF: 0.329 AC: 1145 AN: 3478

EpiCase AF: 0.318

EpiControl AF: 0.322

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

LTA-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 16, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Myocardial infarction, susceptibility to Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Sep 01, 2004

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
Cadd	Benign	15
Dann	Benign	0.95
DEOGEN2	Benign	0.17	T;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.42	N
MetaRNN	Benign	0.00044	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	0.86	P;P
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.010	N;N
REVEL	Benign	0.025
Sift	Benign	0.39	T;T
Sift4G	Uncertain	0.045	D;D
Polyphen		0.0050	B;B
Vest4		0.047
MPC		1.1
ClinPred		0.0010	T
GERP RS		3.1
Varity_R		0.030
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1041981; hg19: chr6-31540784; COSMIC: COSV69304640; COSMIC: COSV69304640;