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GeneBe

rs1041981

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_000595.4(LTA):c.179C>A(p.Thr60Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 1,611,200 control chromosomes in the GnomAD database, including 103,451 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T60A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.38 ( 11465 hom., cov: 28)
Exomes 𝑓: 0.35 ( 91986 hom. )

Consequence

LTA
NM_000595.4 missense

Scores

2
15

Clinical Significance

Benign criteria provided, single submitter B:1O:1

Conservation

PhyloP100: 0.741
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=4.4083595E-4).
BP6
Variant 6-31573007-C-A is Benign according to our data. Variant chr6-31573007-C-A is described in ClinVar as [Benign]. Clinvar id is 14379.Status of the report is criteria_provided_single_submitter, 1 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
LTANM_000595.4 linkuse as main transcriptc.179C>A p.Thr60Asn missense_variant 3/4 ENST00000418386.3
LTANM_001159740.2 linkuse as main transcriptc.179C>A p.Thr60Asn missense_variant 3/4
LTAXM_047418773.1 linkuse as main transcriptc.179C>A p.Thr60Asn missense_variant 5/6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
LTAENST00000418386.3 linkuse as main transcriptc.179C>A p.Thr60Asn missense_variant 3/41 NM_000595.4 P1
LTAENST00000454783.5 linkuse as main transcriptc.179C>A p.Thr60Asn missense_variant 3/42 P1
LTAENST00000471842.1 linkuse as main transcriptn.427C>A non_coding_transcript_exon_variant 2/32
LTAENST00000489638.5 linkuse as main transcriptn.307C>A non_coding_transcript_exon_variant 2/35

Frequencies

GnomAD3 genomes
AF:
0.381
AC:
57634
AN:
151122
Hom.:
11454
Cov.:
28
show subpopulations
Gnomad AFR
AF:
0.502
Gnomad AMI
AF:
0.366
Gnomad AMR
AF:
0.346
Gnomad ASJ
AF:
0.241
Gnomad EAS
AF:
0.471
Gnomad SAS
AF:
0.277
Gnomad FIN
AF:
0.298
Gnomad MID
AF:
0.341
Gnomad NFE
AF:
0.339
Gnomad OTH
AF:
0.350
GnomAD3 exomes
AF:
0.347
AC:
85595
AN:
246840
Hom.:
15475
AF XY:
0.339
AC XY:
45608
AN XY:
134378
show subpopulations
Gnomad AFR exome
AF:
0.501
Gnomad AMR exome
AF:
0.338
Gnomad ASJ exome
AF:
0.241
Gnomad EAS exome
AF:
0.498
Gnomad SAS exome
AF:
0.288
Gnomad FIN exome
AF:
0.300
Gnomad NFE exome
AF:
0.338
Gnomad OTH exome
AF:
0.331
GnomAD4 exome
AF:
0.351
AC:
512722
AN:
1459960
Hom.:
91986
Cov.:
44
AF XY:
0.348
AC XY:
252459
AN XY:
726340
show subpopulations
Gnomad4 AFR exome
AF:
0.508
Gnomad4 AMR exome
AF:
0.336
Gnomad4 ASJ exome
AF:
0.250
Gnomad4 EAS exome
AF:
0.434
Gnomad4 SAS exome
AF:
0.284
Gnomad4 FIN exome
AF:
0.313
Gnomad4 NFE exome
AF:
0.353
Gnomad4 OTH exome
AF:
0.352
GnomAD4 genome
AF:
0.381
AC:
57687
AN:
151240
Hom.:
11465
Cov.:
28
AF XY:
0.377
AC XY:
27836
AN XY:
73858
show subpopulations
Gnomad4 AFR
AF:
0.502
Gnomad4 AMR
AF:
0.346
Gnomad4 ASJ
AF:
0.241
Gnomad4 EAS
AF:
0.471
Gnomad4 SAS
AF:
0.277
Gnomad4 FIN
AF:
0.298
Gnomad4 NFE
AF:
0.339
Gnomad4 OTH
AF:
0.348
Alfa
AF:
0.337
Hom.:
19942
Bravo
AF:
0.391
TwinsUK
AF:
0.375
AC:
1391
ALSPAC
AF:
0.379
AC:
1459
ESP6500AA
AF:
0.511
AC:
1543
ESP6500EA
AF:
0.331
AC:
1793
ExAC
AF:
0.347
AC:
41204
Asia WGS
AF:
0.329
AC:
1145
AN:
3478
EpiCase
AF:
0.318
EpiControl
AF:
0.322

ClinVar

Significance: Benign
Submissions summary: Benign:1Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

LTA-related condition Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesOct 16, 2019This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Myocardial infarction, susceptibility to Other:1
risk factor, no assertion criteria providedliterature onlyOMIMSep 01, 2004- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.060
BayesDel_addAF
Benign
-0.74
T
BayesDel_noAF
Benign
-0.69
Cadd
Benign
15
Dann
Benign
0.95
DEOGEN2
Benign
0.17
T;T
Eigen
Benign
-0.34
Eigen_PC
Benign
-0.26
FATHMM_MKL
Benign
0.42
N
MetaRNN
Benign
0.00044
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.0
M;M
MutationTaster
Benign
0.86
P;P
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-0.010
N;N
REVEL
Benign
0.025
Sift
Benign
0.39
T;T
Sift4G
Uncertain
0.045
D;D
Polyphen
0.0050
B;B
Vest4
0.047
MPC
1.1
ClinPred
0.0010
T
GERP RS
3.1
Varity_R
0.030
gMVP
0.30

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1041981; hg19: chr6-31540784; COSMIC: COSV69304640; COSMIC: COSV69304640; API