rs870849

Variant names:

• chr12-6777854-T-C
• rs870849
• NM_002286.6:c.1364T>C

Your query was ambiguous. Multiple possible variants found:

• chr12-6777854-T-C
• chr12-6777854-T-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.61 (28303 hom., cov: 32)
  • Exomes 𝑓: 0.63 (290510 hom.)
• Consequence: LAG3 NM_002286.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0370
• Publications: 62 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -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	c.1364T>C	p.Ile455Thr	missense_variant	Exon 7 of 8	ENST00000203629.3	NP_002277.4
LAG3	NM_001414176.1	c.1364T>C	p.Ile455Thr	missense_variant	Exon 7 of 8		NP_001401105.1
LAG3	NM_001414177.1	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	Appris	UniProt
LAG3	ENST00000203629.3	c.1364T>C	p.Ile455Thr	missense_variant	Exon 7 of 8	1	NM_002286.6	ENSP00000203629.2
LAG3	ENST00000538079.1	n.1986T>C		non_coding_transcript_exon_variant	Exon 6 of 6	2
LAG3	ENST00000541049.1	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.: 32

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

GnomAD2 exomes AF: 0.641 AC: 160988 AN: 251110 AF XY: 0.637

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 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.: 46 AF XY: 0.627 AC XY: 456199 AN XY: 727022

African (AFR) AF: 0.552 AC: 18461 AN: 33456

American (AMR) AF: 0.699 AC: 31207 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.598 AC: 15621 AN: 26110

East Asian (EAS) AF: 0.835 AC: 33164 AN: 39700

South Asian (SAS) AF: 0.643 AC: 55455 AN: 86240

European-Finnish (FIN) AF: 0.616 AC: 32835 AN: 53338

Middle Eastern (MID) AF: 0.504 AC: 2905 AN: 5766

European-Non Finnish (NFE) AF: 0.621 AC: 690473 AN: 1111742

Other (OTH) AF: 0.633 AC: 38212 AN: 60380

GnomAD4 genome AF: 0.605 AC: 92062 AN: 152056 Hom.: 28303 Cov.: 32 AF XY: 0.607 AC XY: 45116 AN XY: 74354

African (AFR) AF: 0.547 AC: 22676 AN: 41440

American (AMR) AF: 0.634 AC: 9699 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.614 AC: 2129 AN: 3468

East Asian (EAS) AF: 0.836 AC: 4311 AN: 5154

South Asian (SAS) AF: 0.658 AC: 3177 AN: 4826

European-Finnish (FIN) AF: 0.609 AC: 6457 AN: 10604

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.611 AC: 41499 AN: 67954

Other (OTH) AF: 0.616 AC: 1301 AN: 2112

Alfa AF: 0.613 Hom.: 135874

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	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.7
DANN	Benign	0.36
DEOGEN2	Benign	0.098	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	6.3e-7	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.037
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.37	N
REVEL	Benign	0.066
Sift	Benign	0.10	T
Sift4G	Uncertain	0.041	D
Polyphen		0.010	B
Vest4		0.048
MPC		0.11
ClinPred		0.0026	T
GERP RS		-1.6
Varity_R		0.028
gMVP		0.12
Mutation Taster		=91/9	polymorphism (auto)

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: rs870849; hg19: chr12-6887020; COSMIC: COSV52566729; COSMIC: COSV52566729;