rs2229092

chr6-31572980-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000595.4(LTA):c.152A>C(p.His51Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0556 in 1,611,776 control chromosomes in the GnomAD database, including 2,801 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.042 (188 hom., cov: 29)
  • Exomes 𝑓: 0.057 (2613 hom.)
• Consequence: LTA NM_000595.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00500

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019662678).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0617 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LTA	NM_000595.4	c.152A>C	p.His51Pro	missense_variant	3/4	ENST00000418386.3
LTA	NM_001159740.2	c.152A>C	p.His51Pro	missense_variant	3/4
LTA	XM_047418773.1	c.152A>C	p.His51Pro	missense_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LTA	ENST00000418386.3	c.152A>C	p.His51Pro	missense_variant	3/4	1	NM_000595.4	P1
LTA	ENST00000454783.5	c.152A>C	p.His51Pro	missense_variant	3/4	2		P1
LTA	ENST00000471842.1	n.400A>C		non_coding_transcript_exon_variant	2/3	2
LTA	ENST00000489638.5	n.280A>C		non_coding_transcript_exon_variant	2/3	5

Frequencies

GnomAD3 genomes AF: 0.0420 AC: 6343 AN: 150884 Hom.: 189 Cov.: 29

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.0177

Gnomad AMR AF: 0.0354

Gnomad ASJ AF: 0.0237

Gnomad EAS AF: 0.0109

Gnomad SAS AF: 0.0451

Gnomad FIN AF: 0.0548

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0632

Gnomad OTH AF: 0.0531

GnomAD3 exomes AF: 0.0474 AC: 11706 AN: 247216 Hom.: 353 AF XY: 0.0497 AC XY: 6692 AN XY: 134582

Gnomad AFR exome AF: 0.0103

Gnomad AMR exome AF: 0.0297

Gnomad ASJ exome AF: 0.0238

Gnomad EAS exome AF: 0.00957

Gnomad SAS exome AF: 0.0514

Gnomad FIN exome AF: 0.0547

Gnomad NFE exome AF: 0.0637

Gnomad OTH exome AF: 0.0488

GnomAD4 exome AF: 0.0570 AC: 83282 AN: 1460774 Hom.: 2613 Cov.: 36 AF XY: 0.0572 AC XY: 41573 AN XY: 726712

Gnomad4 AFR exome AF: 0.00786

Gnomad4 AMR exome AF: 0.0310

Gnomad4 ASJ exome AF: 0.0254

Gnomad4 EAS exome AF: 0.0141

Gnomad4 SAS exome AF: 0.0537

Gnomad4 FIN exome AF: 0.0536

Gnomad4 NFE exome AF: 0.0626

Gnomad4 OTH exome AF: 0.0498

GnomAD4 genome AF: 0.0420 AC: 6345 AN: 151002 Hom.: 188 Cov.: 29 AF XY: 0.0420 AC XY: 3096 AN XY: 73702

Gnomad4 AFR AF: 0.0111

Gnomad4 AMR AF: 0.0354

Gnomad4 ASJ AF: 0.0237

Gnomad4 EAS AF: 0.0111

Gnomad4 SAS AF: 0.0454

Gnomad4 FIN AF: 0.0548

Gnomad4 NFE AF: 0.0632

Gnomad4 OTH AF: 0.0521

Alfa AF: 0.0591 Hom.: 445

Bravo AF: 0.0381

ESP6500AA AF: 0.0142 AC: 43

ESP6500EA AF: 0.0701 AC: 380

ExAC AF: 0.0479 AC: 5704

Asia WGS AF: 0.0230 AC: 80 AN: 3478

EpiCase AF: 0.0694

EpiControl AF: 0.0691

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.76
Cadd	Benign	5.9
Dann	Benign	0.75
DEOGEN2	Benign	0.34	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.044	N
MetaRNN	Benign	0.0020	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.083
Sift	Benign	0.25	T;T
Sift4G	Benign	0.38	T;T
Polyphen		0.0	B;B
Vest4		0.058
MPC		1.3
ClinPred		0.0019	T
GERP RS		-2.8
Varity_R		0.078
gMVP		0.46

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

Publications

LitVar

Other links and lift over

dbSNP: rs2229092; hg19: chr6-31540757; COSMIC: COSV69305568; COSMIC: COSV69305568;