12-6777854-T-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002286.6(LAG3):​c.1364T>G​(p.Ile455Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I455T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: LAG3 NM_002286.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0370

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1138013).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LAG3	NM_002286.6	c.1364T>G	p.Ile455Ser	missense_variant	Exon 7 of 8	ENST00000203629.3	NP_002277.4
LAG3	NM_001414176.1	c.1364T>G	p.Ile455Ser	missense_variant	Exon 7 of 8		NP_001401105.1
LAG3	NM_001414177.1	c.1121T>G	p.Ile374Ser	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>G	p.Ile455Ser	missense_variant	Exon 7 of 8	1	NM_002286.6	ENSP00000203629.2
LAG3	ENST00000538079.1	n.1986T>G		non_coding_transcript_exon_variant	Exon 6 of 6	2
LAG3	ENST00000541049.1	n.405T>G		non_coding_transcript_exon_variant	Exon 1 of 2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 46

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	6.7
DANN	Benign	0.44
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.0061	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.031
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.22	T
Polyphen		0.012	B
Vest4		0.25
MutPred		0.35		Gain of catalytic residue at V458 (P = 0);
MVP		0.57
MPC		0.13
ClinPred		0.20	T
GERP RS		-1.6
Varity_R		0.077
gMVP		0.27

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: rs870849; hg19: chr12-6887020;