Genetic Variant NM_002286.6:c.512-91G>C (chr12-6774504-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002286.6(LAG3):c.512-91G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.297 in 1,418,704 control chromosomes in the GnomAD database, including 64,224 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.28 ( 6085 hom., cov: 33)

Exomes 𝑓: 0.30 ( 58139 hom. )

Consequence

LAG3
NM_002286.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.11

Publications

9 publications found

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 was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.428 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
LAG3	NM_002286.6 link	c.512-91G>C	intron_variant	Intron 3 of 7	ENST00000203629.3	NP_002277.4	P18627-1
LAG3	NM_001414176.1 link	c.512-91G>C	intron_variant	Intron 3 of 7		NP_001401105.1
LAG3	NM_001414177.1 link	c.512-91G>C	intron_variant	Intron 3 of 6		NP_001401106.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
LAG3	ENST00000203629.3 link	c.512-91G>C	intron_variant	Intron 3 of 7	1	NM_002286.6	ENSP00000203629.2	P18627-1
LAG3	ENST00000441671.6 link	c.512-91G>C	intron_variant	Intron 3 of 4	1		ENSP00000413825.2	P18627-2
LAG3	ENST00000538079.1 link	n.1134-91G>C	intron_variant	Intron 2 of 5	2

Frequencies

GnomAD3 genomes

AF:

0.279

AC:

42473

AN:

152018

Hom.:

6078

Cov.:

show subpopulations

Gnomad AFR

AF:

0.216

Gnomad AMI

AF:

0.239

Gnomad AMR

AF:

0.318

Gnomad ASJ

AF:

0.240

Gnomad EAS

AF:

0.444

Gnomad SAS

AF:

0.347

Gnomad FIN

AF:

0.308

Gnomad MID

AF:

0.168

Gnomad NFE

AF:

0.291

Gnomad OTH

AF:

0.266

GnomAD4 exome

AF:

0.299

AC:

379331

AN:

1266568

Hom.:

58139

AF XY:

0.299

AC XY:

187542

AN XY:

627678

show subpopulations

African (AFR)

AF:

0.210

AC:

5997

AN:

28624

American (AMR)

AF:

0.348

AC:

11116

AN:

31958

Ashkenazi Jewish (ASJ)

AF:

0.251

AC:

5028

AN:

20060

East Asian (EAS)

AF:

0.444

AC:

17071

AN:

38408

South Asian (SAS)

AF:

0.322

AC:

22594

AN:

70164

European-Finnish (FIN)

AF:

0.309

AC:

12265

AN:

39748

Middle Eastern (MID)

AF:

0.201

AC:

975

AN:

4862

European-Non Finnish (NFE)

AF:

0.294

AC:

288462

AN:

979524

Other (OTH)

AF:

0.297

AC:

15823

AN:

53220

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

13420

26841

40261

53682

67102

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9670

19340

29010

38680

48350

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.279

AC:

42508

AN:

152136

Hom.:

6085

Cov.:

AF XY:

0.283

AC XY:

21031

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.216

AC:

8983

AN:

41520

American (AMR)

AF:

0.319

AC:

4877

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.240

AC:

832

AN:

3472

East Asian (EAS)

AF:

0.443

AC:

2289

AN:

5164

South Asian (SAS)

AF:

0.346

AC:

1672

AN:

4828

European-Finnish (FIN)

AF:

0.308

AC:

3268

AN:

10602

Middle Eastern (MID)

AF:

0.170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.291

AC:

19757

AN:

67946

Other (OTH)

AF:

0.266

AC:

562

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1568

3136

4703

6271

7839

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

428

856

1284

1712

2140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.289

Hom.:

823

Bravo

AF:

0.271

Asia WGS

AF:

0.385

AC:

1337

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.41

(source)

DANN

Benign

0.62

PhyloP100

-1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over