dbSNP rs870849: LAG3:p.Ile455Thr (chr12-6777854-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002286.6(LAG3):c.1364T>C(p.Ile455Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.626 in 1,613,406 control chromosomes in the GnomAD database, including 318,813 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.61 ( 28303 hom., cov: 32)

Exomes 𝑓: 0.63 ( 290510 hom. )

Consequence

LAG3
NM_002286.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0370

Variant links:

Genes affected

LAG3 (HGNC:6476): (lymphocyte activating 3) Lymphocyte-activation protein 3 belongs to Ig superfamily and contains 4 extracellular Ig-like domains. The LAG3 gene contains 8 exons. The sequence data, exon/intron organization, and chromosomal localization all indicate a close relationship of LAG3 to CD4. [provided by RefSeq, Jul 2008]

LAG3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=6.271263E-7).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.816 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAG3	NM_002286.6 link	c.1364T>C	p.Ile455Thr	missense_variant	Exon 7 of 8	ENST00000203629.3	NP_002277.4	P18627-1
LAG3	NM_001414176.1 link	c.1364T>C	p.Ile455Thr	missense_variant	Exon 7 of 8		NP_001401105.1
LAG3	NM_001414177.1 link	c.1121T>C	p.Ile374Thr	missense_variant	Exon 6 of 7		NP_001401106.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LAG3	ENST00000203629.3 link	c.1364T>C	p.Ile455Thr	missense_variant	Exon 7 of 8	1	NM_002286.6	ENSP00000203629.2	P18627-1
LAG3	ENST00000538079.1 link	n.1986T>C		non_coding_transcript_exon_variant	Exon 6 of 6	2
LAG3	ENST00000541049.1 link	n.405T>C		non_coding_transcript_exon_variant	Exon 1 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.605

AC:

91985

AN:

151938

Hom.:

28273

Cov.:

show subpopulations

Gnomad AFR

AF:

0.547

Gnomad AMI

AF:

0.737

Gnomad AMR

AF:

0.634

Gnomad ASJ

AF:

0.614

Gnomad EAS

AF:

0.838

Gnomad SAS

AF:

0.660

Gnomad FIN

AF:

0.609

Gnomad MID

AF:

0.487

Gnomad NFE

AF:

0.611

Gnomad OTH

AF:

0.612

GnomAD3 exomes

AF:

0.641

AC:

160988

AN:

251110

Hom.:

52381

AF XY:

0.637

AC XY:

86452

AN XY:

135724

show subpopulations

Gnomad AFR exome

AF:

0.547

Gnomad AMR exome

AF:

0.705

Gnomad ASJ exome

AF:

0.591

Gnomad EAS exome

AF:

0.842

Gnomad SAS exome

AF:

0.644

Gnomad FIN exome

AF:

0.615

Gnomad NFE exome

AF:

0.612

Gnomad OTH exome

AF:

0.625

GnomAD4 exome

AF:

0.628

AC:

918333

AN:

1461350

Hom.:

290510

Cov.:

AF XY:

0.627

AC XY:

456199

AN XY:

727022

show subpopulations

Gnomad4 AFR exome

AF:

0.552

Gnomad4 AMR exome

AF:

0.699

Gnomad4 ASJ exome

AF:

0.598

Gnomad4 EAS exome

AF:

0.835

Gnomad4 SAS exome

AF:

0.643

Gnomad4 FIN exome

AF:

0.616

Gnomad4 NFE exome

AF:

0.621

Gnomad4 OTH exome

AF:

0.633

GnomAD4 genome

AF:

0.605

AC:

92062

AN:

152056

Hom.:

28303

Cov.:

AF XY:

0.607

AC XY:

45116

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.547

Gnomad4 AMR

AF:

0.634

Gnomad4 ASJ

AF:

0.614

Gnomad4 EAS

AF:

0.836

Gnomad4 SAS

AF:

0.658

Gnomad4 FIN

AF:

0.609

Gnomad4 NFE

AF:

0.611

Gnomad4 OTH

AF:

0.616

Alfa

AF:

0.612

Hom.:

72621

Bravo

AF:

0.608

TwinsUK

AF:

0.622

AC:

2306

ALSPAC

AF:

0.646

AC:

2491

ESP6500AA

AF:

0.555

AC:

2446

ESP6500EA

AF:

0.621

AC:

5337

ExAC

AF:

0.639

AC:

77604

Asia WGS

AF:

0.748

AC:

2604

AN:

3478

EpiCase

AF:

0.590

EpiControl

AF:

0.593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.76

CADD

Benign

2.7

DANN

Benign

0.36

DEOGEN2

Benign

0.098

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.33

MetaRNN

Benign

6.3e-7

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.37

REVEL

Benign

0.066

Sift

Benign

0.10

Sift4G

Uncertain

0.041

Polyphen

0.010

Vest4

0.048

MPC

0.11

ClinPred

0.0026

GERP RS

-1.6

Varity_R

0.028

gMVP

0.12

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over