rs2229094

Positions:

• chr6-31572779-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 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 (no stars). 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 no assertion criteria provided 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 -13 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 no_assertion_criteria_provided, 0 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	Protein	UniProt
LTA	NM_000595.4	c.37T>C	p.Cys13Arg	missense_variant	2/4	ENST00000418386.3	NP_000586.2
LTA	NM_001159740.2	c.37T>C	p.Cys13Arg	missense_variant	2/4		NP_001153212.1
LTA	XM_047418773.1	c.37T>C	p.Cys13Arg	missense_variant	4/6		XP_047274729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LTA	ENST00000418386.3	c.37T>C	p.Cys13Arg	missense_variant	2/4	1	NM_000595.4	ENSP00000413450	P1
LTA	ENST00000454783.5	c.37T>C	p.Cys13Arg	missense_variant	2/4	2		ENSP00000403495	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: no assertion criteria provided

Submissions by phenotype

LTA-related disorder Benign:1

Benign, no assertion criteria provided

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;