rs2229094

Variant names:

• chr6-31572779-T-C
• rs2229094
• NM_000595.4:c.37T>C

Variant summary

Our verdict is Benign. The variant received -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. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• 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
• Publications: 176 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]

ENSG00000289406 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTA	NM_000595.4	MANE Select	c.37T>C	p.Cys13Arg	missense	Exon 2 of 4	NP_000586.2
	LTA	NM_001159740.2		c.37T>C	p.Cys13Arg	missense	Exon 2 of 4	NP_001153212.1
	LOC100287329	NR_149045.1		n.-76A>G		upstream_gene	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTA	ENST00000418386.3	TSL:1 MANE Select	c.37T>C	p.Cys13Arg	missense	Exon 2 of 4	ENSP00000413450.2
	LTA	ENST00000454783.5	TSL:2	c.37T>C	p.Cys13Arg	missense	Exon 2 of 4	ENSP00000403495.1
	LTA	ENST00000877327.1		c.37T>C	p.Cys13Arg	missense	Exon 1 of 3	ENSP00000547386.1

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

GnomAD2 exomes AF: 0.268 AC: 65640 AN: 245246 AF XY: 0.274

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 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

African (AFR) AF: 0.280 AC: 9370 AN: 33464

American (AMR) AF: 0.214 AC: 9584 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.300 AC: 7827 AN: 26118

East Asian (EAS) AF: 0.184 AC: 7314 AN: 39696

South Asian (SAS) AF: 0.334 AC: 28808 AN: 86250

European-Finnish (FIN) AF: 0.329 AC: 16645 AN: 50558

Middle Eastern (MID) AF: 0.292 AC: 1685 AN: 5762

European-Non Finnish (NFE) AF: 0.256 AC: 284633 AN: 1111400

Other (OTH) AF: 0.271 AC: 16372 AN: 60344

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

African (AFR) AF: 0.278 AC: 11427 AN: 41144

American (AMR) AF: 0.241 AC: 3674 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.295 AC: 1024 AN: 3470

East Asian (EAS) AF: 0.194 AC: 981 AN: 5052

South Asian (SAS) AF: 0.335 AC: 1593 AN: 4756

European-Finnish (FIN) AF: 0.341 AC: 3577 AN: 10504

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.262 AC: 17763 AN: 67774

Other (OTH) AF: 0.301 AC: 631 AN: 2094

Alfa AF: 0.266 Hom.: 23778

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

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	LTA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0068	N
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.81	N
PhyloP100		-0.60
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.037
Sift	Benign	0.78	T
Sift4G	Benign	0.46	T
Polyphen		0.0	B
Vest4		0.046
MPC		1.4
ClinPred		0.0021	T
GERP RS		1.3
PromoterAI		-0.053	Neutral
Varity_R		0.22
gMVP		0.56
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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