rs2229094

chr6-31572779-T-C

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.37T>C(p.Cys13Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.263 in 1,609,528 control chromosomes in the GnomAD database, including 56,590 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.27 (5620 hom., cov: 28)
  • Exomes 𝑓: 0.26 (50970 hom.)
• Consequence: LTA NM_000595.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.598

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=0.005508542).
• BP6: Variant 6-31572779-T-C is Benign according to our data. Variant chr6-31572779-T-C is described in ClinVar as [Benign]. Clinvar id is 3059641.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LTA	NM_000595.4	c.37T>C	p.Cys13Arg	missense_variant	2/4	ENST00000418386.3
LTA	NM_001159740.2	c.37T>C	p.Cys13Arg	missense_variant	2/4
LTA	XM_047418773.1	c.37T>C	p.Cys13Arg	missense_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LTA	ENST00000418386.3	c.37T>C	p.Cys13Arg	missense_variant	2/4	1	NM_000595.4	P1
LTA	ENST00000454783.5	c.37T>C	p.Cys13Arg	missense_variant	2/4	2		P1
LTA	ENST00000471842.1	n.199T>C		non_coding_transcript_exon_variant	2/3	2
LTA	ENST00000489638.5	n.79T>C		non_coding_transcript_exon_variant	2/3	5

Frequencies

GnomAD3 genomes AF: 0.271 AC: 41010 AN: 151112 Hom.: 5617 Cov.: 28

Gnomad AFR AF: 0.277

Gnomad AMI AF: 0.307

Gnomad AMR AF: 0.241

Gnomad ASJ AF: 0.295

Gnomad EAS AF: 0.194

Gnomad SAS AF: 0.336

Gnomad FIN AF: 0.341

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.262

Gnomad OTH AF: 0.303

GnomAD3 exomes AF: 0.268 AC: 65640 AN: 245246 Hom.: 9119 AF XY: 0.274 AC XY: 36602 AN XY: 133738

Gnomad AFR exome AF: 0.276

Gnomad AMR exome AF: 0.205

Gnomad ASJ exome AF: 0.301

Gnomad EAS exome AF: 0.193

Gnomad SAS exome AF: 0.326

Gnomad FIN exome AF: 0.336

Gnomad NFE exome AF: 0.267

Gnomad OTH exome AF: 0.268

GnomAD4 exome AF: 0.262 AC: 382238 AN: 1458298 Hom.: 50970 Cov.: 43 AF XY: 0.265 AC XY: 192001 AN XY: 725518

Gnomad4 AFR exome AF: 0.280

Gnomad4 AMR exome AF: 0.214

Gnomad4 ASJ exome AF: 0.300

Gnomad4 EAS exome AF: 0.184

Gnomad4 SAS exome AF: 0.334

Gnomad4 FIN exome AF: 0.329

Gnomad4 NFE exome AF: 0.256

Gnomad4 OTH exome AF: 0.271

GnomAD4 genome AF: 0.271 AC: 41048 AN: 151230 Hom.: 5620 Cov.: 28 AF XY: 0.275 AC XY: 20275 AN XY: 73826

Gnomad4 AFR AF: 0.278

Gnomad4 AMR AF: 0.241

Gnomad4 ASJ AF: 0.295

Gnomad4 EAS AF: 0.194

Gnomad4 SAS AF: 0.335

Gnomad4 FIN AF: 0.341

Gnomad4 NFE AF: 0.262

Gnomad4 OTH AF: 0.301

Alfa AF: 0.268 Hom.: 11585

Bravo AF: 0.264

TwinsUK AF: 0.252 AC: 936

ALSPAC AF: 0.249 AC: 960

ESP6500AA AF: 0.281 AC: 849

ESP6500EA AF: 0.270 AC: 1465

ExAC AF: 0.269 AC: 31695

Asia WGS AF: 0.290 AC: 1007 AN: 3478

EpiCase AF: 0.274

EpiControl AF: 0.280

ClinVar

Significance: Benign

Submissions summary: Benign: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 17, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	7.3
Dann	Benign	0.76
DEOGEN2	Benign	0.23	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0068	N
MetaRNN	Benign	0.0055	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.81	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.56	N;N
REVEL	Benign	0.037
Sift	Benign	0.78	T;T
Sift4G	Benign	0.46	T;T
Polyphen		0.0	B;B
Vest4		0.046
MPC		1.4
ClinPred		0.0021	T
GERP RS		1.3
Varity_R		0.22
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: -4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2229094; hg19: chr6-31540556; COSMIC: COSV69304469; COSMIC: COSV69304469;