12-6773857-G-T

Variant summary

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

The NM_002286.6(LAG3):c.367G>T(p.Asp123Tyr) 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LAG3 NM_002286.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00500

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=0.16132775).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAG3	NM_002286.6	c.367G>T	p.Asp123Tyr	missense_variant	3/8	ENST00000203629.3
LAG3	NM_001414176.1	c.367G>T	p.Asp123Tyr	missense_variant	3/8
LAG3	NM_001414177.1	c.367G>T	p.Asp123Tyr	missense_variant	3/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAG3	ENST00000203629.3	c.367G>T	p.Asp123Tyr	missense_variant	3/8	1	NM_002286.6	P2
LAG3	ENST00000441671.6	c.367G>T	p.Asp123Tyr	missense_variant	3/5	1		A2
LAG3	ENST00000538079.1	n.989G>T		non_coding_transcript_exon_variant	2/6	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1253962 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 614174

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

May 01, 2022

The c.367G>T (p.D123Y) alteration is located in exon 3 (coding exon 3) of the LAG3 gene. This alteration results from a G to T substitution at nucleotide position 367, causing the aspartic acid (D) at amino acid position 123 to be replaced by a tyrosine (Y). 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	0.29
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	19
Dann	Uncertain	0.99
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.094
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.64	T;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	0.52	D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-2.2	N;N
REVEL	Benign	0.11
Sift	Uncertain	0.024	D;D
Sift4G	Uncertain	0.029	D;D
Polyphen		0.45	.;P
Vest4		0.13
MutPred		0.38		Gain of MoRF binding (P = 0.0394);Gain of MoRF binding (P = 0.0394);
MVP		0.56
MPC		0.12
ClinPred		0.51	D
GERP RS		4.3
Varity_R		0.15
gMVP		0.35

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: rs1454875127; hg19: chr12-6883023;