rs2229699

Positions:

• chr6-31581079-G-A
• chr6-31581079-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_002341.2(LTB):​c.365C>T​(p.Ala122Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,610,968 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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. A122D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0022 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (29 hom.)
• Consequence: LTB NM_002341.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.63

Genes affected

LTB (HGNC:6711): (lymphotoxin beta) Lymphotoxin beta is a type II membrane protein of the TNF family. It anchors lymphotoxin-alpha to the cell surface through heterotrimer formation. The predominant form on the lymphocyte surface is the lymphotoxin-alpha 1/beta 2 complex (e.g. 1 molecule alpha/2 molecules beta) and this complex is the primary ligand for the lymphotoxin-beta receptor. The minor complex is lymphotoxin-alpha 2/beta 1. LTB is an inducer of the inflammatory response system and involved in normal development of lymphoid tissue. Lymphotoxin-beta isoform b is unable to complex with lymphotoxin-alpha suggesting a function for lymphotoxin-beta which is independent of lympyhotoxin-alpha. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005446583).
• BP6: Variant 6-31581079-G-A is Benign according to our data. Variant chr6-31581079-G-A is described in ClinVar as [Benign]. Clinvar id is 770169.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LTB	NM_002341.2	c.365C>T	p.Ala122Val	missense_variant	4/4	ENST00000429299.3
LTB	NM_009588.1	c.*85C>T		3_prime_UTR_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LTB	ENST00000429299.3	c.365C>T	p.Ala122Val	missense_variant	4/4	1	NM_002341.2	P1
LTB	ENST00000446745.2	c.*85C>T		3_prime_UTR_variant	3/3	1
LTB	ENST00000482429.1	n.933C>T		non_coding_transcript_exon_variant	2/2	2
LTB	ENST00000483972.1	n.184C>T		non_coding_transcript_exon_variant	3/3	5

Frequencies

GnomAD3 genomes AF: 0.00222 AC: 338 AN: 152262 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00902

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.0133

Gnomad SAS AF: 0.00848

Gnomad FIN AF: 0.00216

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00449 AC: 1077 AN: 240128 Hom.: 9 AF XY: 0.00394 AC XY: 519 AN XY: 131594

Gnomad AFR exome AF: 0.000608

Gnomad AMR exome AF: 0.0141

Gnomad ASJ exome AF: 0.00614

Gnomad EAS exome AF: 0.0162

Gnomad SAS exome AF: 0.00513

Gnomad FIN exome AF: 0.00113

Gnomad NFE exome AF: 0.000479

Gnomad OTH exome AF: 0.00202

GnomAD4 exome AF: 0.00165 AC: 2402 AN: 1458588 Hom.: 29 Cov.: 31 AF XY: 0.00175 AC XY: 1273 AN XY: 725600

Gnomad4 AFR exome AF: 0.000419

Gnomad4 AMR exome AF: 0.0139

Gnomad4 ASJ exome AF: 0.00619

Gnomad4 EAS exome AF: 0.0145

Gnomad4 SAS exome AF: 0.00557

Gnomad4 FIN exome AF: 0.00144

Gnomad4 NFE exome AF: 0.000248

Gnomad4 OTH exome AF: 0.00340

GnomAD4 genome AF: 0.00224 AC: 341 AN: 152380 Hom.: 4 Cov.: 32 AF XY: 0.00243 AC XY: 181 AN XY: 74520

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.00914

Gnomad4 ASJ AF: 0.00662

Gnomad4 EAS AF: 0.0133

Gnomad4 SAS AF: 0.00849

Gnomad4 FIN AF: 0.00216

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00139 Hom.: 5

Bravo AF: 0.00255

ESP6500AA AF: 0.000332 AC: 1

ESP6500EA AF: 0.000185 AC: 1

ExAC AF: 0.00396 AC: 462

Asia WGS AF: 0.0150 AC: 53 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000830

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.059	N
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.049
Sift	Benign	0.079	T
Sift4G	Benign	0.19	T
Polyphen		0.19	B
Vest4		0.17
MVP		0.67
MPC		1.5
ClinPred		0.019	T
GERP RS		4.5
Varity_R		0.22
gMVP		0.29

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: rs2229699; hg19: chr6-31548856;