Variant 12-6773714-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002286.6(LAG3):c.224C>A(p.Ala75Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000017 in 1,353,424 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

LAG3
NM_002286.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.420

Variant links:

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]

LAG3 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.037047327).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
LAG3	NM_002286.6 linkuse as main transcript	c.224C>A	p.Ala75Asp	missense_variant	3/8	ENST00000203629.3	NP_002277.4
LAG3	NM_001414176.1 linkuse as main transcript	c.224C>A	p.Ala75Asp	missense_variant	3/8		NP_001401105.1
LAG3	NM_001414177.1 linkuse as main transcript	c.224C>A	p.Ala75Asp	missense_variant	3/7		NP_001401106.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LAG3	ENST00000203629.3 linkuse as main transcript	c.224C>A	p.Ala75Asp	missense_variant	3/8	1	NM_002286.6	ENSP00000203629	P2	P18627-1
LAG3	ENST00000441671.6 linkuse as main transcript	c.224C>A	p.Ala75Asp	missense_variant	3/5	1		ENSP00000413825	A2	P18627-2
LAG3	ENST00000538079.1 linkuse as main transcript	n.846C>A		non_coding_transcript_exon_variant	2/6	2

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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

GnomAD3 exomes

AF:

0.0000413

AC:

AN:

48448

Hom.:

AF XY:

0.0000363

AC XY:

AN XY:

27546

show subpopulations

Gnomad AFR exome

AF:

0.000296

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000337

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000125

AC:

AN:

1201140

Hom.:

Cov.:

AF XY:

0.0000104

AC XY:

AN XY:

579552

show subpopulations

Gnomad4 AFR exome

AF:

0.000407

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000344

Gnomad4 SAS exome

AF:

0.0000227

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000101

Gnomad4 OTH exome

AF:

0.0000407

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000831

ExAC

AF:

0.0000196

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 16, 2022

The c.224C>A (p.A75D) alteration is located in exon 3 (coding exon 3) of the LAG3 gene. This alteration results from a C to A substitution at nucleotide position 224, causing the alanine (A) at amino acid position 75 to be replaced by an aspartic acid (D). 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

0.099

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.70

CADD

Benign

6.6

DANN

Benign

0.87

DEOGEN2

Benign

0.12

.;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0096

LIST_S2

Benign

0.27

T;T

M_CAP

Benign

0.011

MetaRNN

Benign

0.037

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.34

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.013

Sift

Benign

0.44

T;T

Sift4G

Benign

0.64

T;T

Polyphen

0.032

.;B

Vest4

0.20

MutPred

0.33

Gain of catalytic residue at G70 (P = 0.0016);Gain of catalytic residue at G70 (P = 0.0016);

MVP

0.25

MPC

0.15

ClinPred

0.012

GERP RS

-2.1

Varity_R

0.092

gMVP

0.36

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over