12-6774743-C-G

Position:

• chr12-6774743-C-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.660C>G​(p.His220Gln) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LAG3 NM_002286.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.530

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=0.17232493).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LAG3	NM_002286.6	c.660C>G	p.His220Gln	missense_variant	4/8	ENST00000203629.3	NP_002277.4
LAG3	NM_001414176.1	c.660C>G	p.His220Gln	missense_variant	4/8		NP_001401105.1
LAG3	NM_001414177.1	c.660C>G	p.His220Gln	missense_variant	4/7		NP_001401106.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAG3	ENST00000203629.3	c.660C>G	p.His220Gln	missense_variant	4/8	1	NM_002286.6	ENSP00000203629	P2
LAG3	ENST00000441671.6	c.660C>G	p.His220Gln	missense_variant	4/5	1		ENSP00000413825	A2
LAG3	ENST00000538079.1	n.1282C>G		non_coding_transcript_exon_variant	3/6	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

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

Aug 03, 2022

The c.660C>G (p.H220Q) alteration is located in exon 4 (coding exon 4) of the LAG3 gene. This alteration results from a C to G substitution at nucleotide position 660, causing the histidine (H) at amino acid position 220 to be replaced by a glutamine (Q). 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	0.23
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.073	.;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.61	T;T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.049
Sift	Benign	0.35	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.97	.;D
Vest4		0.38
MutPred		0.30		Gain of catalytic residue at E223 (P = 0.0035);Gain of catalytic residue at E223 (P = 0.0035);
MVP		0.45
MPC		0.38
ClinPred		0.40	T
GERP RS		2.1
Varity_R		0.079
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-6883909;