rs3093546

Variant names:

• chr6-31572365-G-A
• rs3093546
• NM_000595.4:c.-91G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000595.4(LTA):​c.-91G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.033 in 361,008 control chromosomes in the GnomAD database, including 290 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.030 (108 hom., cov: 32)
  • Exomes 𝑓: 0.035 (182 hom.)
• Consequence: LTA NM_000595.4 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.60
• Publications: 9 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 (BayesDel_noAF=-0.86).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0304 (4634/152260) while in subpopulation NFE AF = 0.0463 (3149/68004). AF 95% confidence interval is 0.045. There are 108 homozygotes in GnomAd4. There are 2176 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 108 gene

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.-91G>A		5_prime_UTR	Exon 1 of 4	NP_000586.2
	LTA	NM_001159740.2		c.-10+63G>A		intron	N/A	NP_001153212.1
	LOC100287329	NR_149045.1		n.121+218C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTA	ENST00000418386.3	TSL:1 MANE Select	c.-91G>A		5_prime_UTR	Exon 1 of 4	ENSP00000413450.2
	LTA	ENST00000471842.1	TSL:2	n.72G>A		non_coding_transcript_exon	Exon 1 of 3
	LTA	ENST00000454783.5	TSL:2	c.-10+63G>A		intron	N/A	ENSP00000403495.1

Frequencies

GnomAD3 genomes AF: 0.0305 AC: 4635 AN: 152142 Hom.: 108 Cov.: 32

Gnomad AFR AF: 0.00736

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0317

Gnomad ASJ AF: 0.0204

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.0407

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0463

Gnomad OTH AF: 0.0317

GnomAD4 exome AF: 0.0348 AC: 7267 AN: 208748 Hom.: 182 Cov.: 0 AF XY: 0.0336 AC XY: 3648 AN XY: 108444

African (AFR) AF: 0.00578 AC: 36 AN: 6232

American (AMR) AF: 0.0246 AC: 171 AN: 6956

Ashkenazi Jewish (ASJ) AF: 0.0152 AC: 107 AN: 7028

East Asian (EAS) AF: 0.00452 AC: 70 AN: 15502

South Asian (SAS) AF: 0.00889 AC: 144 AN: 16206

European-Finnish (FIN) AF: 0.0410 AC: 575 AN: 14038

Middle Eastern (MID) AF: 0.0146 AC: 15 AN: 1024

European-Non Finnish (NFE) AF: 0.0441 AC: 5690 AN: 128942

Other (OTH) AF: 0.0358 AC: 459 AN: 12820

GnomAD4 genome AF: 0.0304 AC: 4634 AN: 152260 Hom.: 108 Cov.: 32 AF XY: 0.0292 AC XY: 2176 AN XY: 74434

African (AFR) AF: 0.00734 AC: 305 AN: 41554

American (AMR) AF: 0.0317 AC: 485 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0204 AC: 71 AN: 3472

East Asian (EAS) AF: 0.00309 AC: 16 AN: 5180

South Asian (SAS) AF: 0.0126 AC: 61 AN: 4824

European-Finnish (FIN) AF: 0.0407 AC: 432 AN: 10612

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0463 AC: 3149 AN: 68004

Other (OTH) AF: 0.0313 AC: 66 AN: 2106

Alfa AF: 0.0399 Hom.: 89

Bravo AF: 0.0283

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.092
DANN	Benign	0.52
PhyloP100		-2.6
PromoterAI		-0.0014	Neutral
Mutation Taster		=300/0	polymorphism

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: rs3093546; hg19: chr6-31540142;