rs2229092

Variant names:

• chr6-31572980-A-C
• rs2229092
• NM_000595.4:c.152A>C

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. H51N) has been classified as Uncertain significance.

• 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
• Publications: 65 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 -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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTA	NM_000595.4	MANE Select	c.152A>C	p.His51Pro	missense	Exon 3 of 4	NP_000586.2
	LTA	NM_001159740.2		c.152A>C	p.His51Pro	missense	Exon 3 of 4	NP_001153212.1	Q5STV3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTA	ENST00000418386.3	TSL:1 MANE Select	c.152A>C	p.His51Pro	missense	Exon 3 of 4	ENSP00000413450.2	P01374
	LTA	ENST00000454783.5	TSL:2	c.152A>C	p.His51Pro	missense	Exon 3 of 4	ENSP00000403495.1	P01374
	LTA	ENST00000877327.1		c.152A>C	p.His51Pro	missense	Exon 2 of 3	ENSP00000547386.1

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

GnomAD2 exomes AF: 0.0474 AC: 11706 AN: 247216 AF XY: 0.0497

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 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

African (AFR) AF: 0.00786 AC: 263 AN: 33480

American (AMR) AF: 0.0310 AC: 1384 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0254 AC: 665 AN: 26132

East Asian (EAS) AF: 0.0141 AC: 561 AN: 39700

South Asian (SAS) AF: 0.0537 AC: 4634 AN: 86258

European-Finnish (FIN) AF: 0.0536 AC: 2811 AN: 52420

Middle Eastern (MID) AF: 0.0635 AC: 366 AN: 5768

European-Non Finnish (NFE) AF: 0.0626 AC: 69592 AN: 1111916

Other (OTH) AF: 0.0498 AC: 3006 AN: 60384

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

African (AFR) AF: 0.0111 AC: 454 AN: 41070

American (AMR) AF: 0.0354 AC: 538 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.0237 AC: 82 AN: 3462

East Asian (EAS) AF: 0.0111 AC: 56 AN: 5054

South Asian (SAS) AF: 0.0454 AC: 216 AN: 4762

European-Finnish (FIN) AF: 0.0548 AC: 574 AN: 10472

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0632 AC: 4280 AN: 67672

Other (OTH) AF: 0.0521 AC: 109 AN: 2094

Alfa AF: 0.0551 Hom.: 953

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 v4.9

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
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.044	N
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.0050
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.083
Sift	Benign	0.25	T
Sift4G	Benign	0.38	T
Polyphen		0.0	B
Vest4		0.058
MPC		1.3
ClinPred		0.0019	T
GERP RS		-2.8
Varity_R		0.078
gMVP		0.46
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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