12-6775278-G-A

Variant summary

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

The NM_002286.6(LAG3):c.787G>A(p.Glu263Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: LAG3 NM_002286.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.566

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=0.23557577).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAG3	NM_002286.6	c.787G>A	p.Glu263Lys	missense_variant	5/8	ENST00000203629.3
LAG3	NM_001414176.1	c.787G>A	p.Glu263Lys	missense_variant	5/8
LAG3	NM_001414177.1	c.787G>A	p.Glu263Lys	missense_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAG3	ENST00000203629.3	c.787G>A	p.Glu263Lys	missense_variant	5/8	1	NM_002286.6	P2
LAG3	ENST00000441671.6	c.787G>A	p.Glu263Lys	missense_variant	5/5	1		A2
LAG3	ENST00000538079.1	n.1409G>A		non_coding_transcript_exon_variant	4/6	2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152124 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152124 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74300

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 05, 2022

The c.787G>A (p.E263K) alteration is located in exon 5 (coding exon 5) of the LAG3 gene. This alteration results from a G to A substitution at nucleotide position 787, causing the glutamic acid (E) at amino acid position 263 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	20
Dann	Uncertain	1.0
Eigen	Benign	0.10
Eigen_PC	Benign	0.056
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.85	D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	0.71	D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.16
Sift	Benign	0.076	T;D
Sift4G	Uncertain	0.013	D;D
Polyphen		1.0	.;D
Vest4		0.41
MutPred		0.47		Gain of catalytic residue at E263 (P = 0);Gain of catalytic residue at E263 (P = 0);
MVP		0.53
MPC		0.40
ClinPred		0.95	D
GERP RS		4.7
Varity_R		0.13
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1352954057; hg19: chr12-6884444;