NM_000595.4:c.-9-82C>A

Variant names:

• chr6-31572652-C-A
• rs746868
• NM_000595.4:c.-9-82C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000595.4(LTA):​c.-9-82C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000232 in 949,358 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000014 (0 hom., cov: 23)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: LTA NM_000595.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.115
• Publications: 47 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).

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.-9-82C>A		intron	N/A	NP_000586.2
	LOC100287329	NR_149045.1		n.52G>T		non_coding_transcript_exon	Exon 1 of 2
	LTA	NM_001159740.2		c.-9-82C>A		intron	N/A	NP_001153212.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTA	ENST00000418386.3	TSL:1 MANE Select	c.-9-82C>A		intron	N/A	ENSP00000413450.2
	ENSG00000289406	ENST00000691266.2		n.130G>T		non_coding_transcript_exon	Exon 1 of 2
	LTA	ENST00000454783.5	TSL:2	c.-9-82C>A		intron	N/A	ENSP00000403495.1

Frequencies

GnomAD3 genomes AF: 0.0000136 AC: 2 AN: 147240 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000151

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000249 AC: 20 AN: 802118 Hom.: 0 Cov.: 11 AF XY: 0.0000216 AC XY: 9 AN XY: 416880

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 20708

American (AMR) AF: 0.000107 AC: 4 AN: 37218

Ashkenazi Jewish (ASJ) AF: 0.0000522 AC: 1 AN: 19170

East Asian (EAS) AF: 0.00 AC: 0 AN: 35886

South Asian (SAS) AF: 0.0000304 AC: 2 AN: 65694

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35788

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4364

European-Non Finnish (NFE) AF: 0.0000220 AC: 12 AN: 544966

Other (OTH) AF: 0.0000261 AC: 1 AN: 38324

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000136 AC: 2 AN: 147240 Hom.: 0 Cov.: 23 AF XY: 0.0000279 AC XY: 2 AN XY: 71740

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000251 AC: 1 AN: 39848

American (AMR) AF: 0.00 AC: 0 AN: 14882

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3382

East Asian (EAS) AF: 0.00 AC: 0 AN: 4860

South Asian (SAS) AF: 0.00 AC: 0 AN: 4582

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000151 AC: 1 AN: 66320

Other (OTH) AF: 0.00 AC: 0 AN: 2010

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.6
DANN	Benign	0.40
PhyloP100		0.12
PromoterAI		0.043	Neutral

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: rs746868; hg19: chr6-31540429;