12-6772917-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_002286.6(LAG3):c.58+7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00499 in 1,613,656 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0039 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (21 hom.)
• Consequence: LAG3 NM_002286.6 splice_region, intron
• Scores: Splicing: ADA: 0.0002742
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.60

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 12-6772917-C-T is Benign according to our data. Variant chr12-6772917-C-T is described in ClinVar as [Benign]. Clinvar id is 789317.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LAG3	NM_002286.6	c.58+7C>T		splice_region_variant, intron_variant		ENST00000203629.3
LAG3	NM_001414176.1	c.58+7C>T		splice_region_variant, intron_variant
LAG3	NM_001414177.1	c.58+7C>T		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LAG3	ENST00000203629.3	c.58+7C>T		splice_region_variant, intron_variant		1	NM_002286.6	P2
LAG3	ENST00000441671.6	c.58+7C>T		splice_region_variant, intron_variant		1		A2
LAG3	ENST00000538079.1	n.406C>T		non_coding_transcript_exon_variant	1/6	2

Frequencies

GnomAD3 genomes AF: 0.00394 AC: 599 AN: 151990 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00420

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00530

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00606

Gnomad OTH AF: 0.00623

GnomAD3 exomes AF: 0.00365 AC: 917 AN: 250956 Hom.: 6 AF XY: 0.00346 AC XY: 470 AN XY: 135660

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00101

Gnomad FIN exome AF: 0.00516

Gnomad NFE exome AF: 0.00565

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00510 AC: 7451 AN: 1461548 Hom.: 21 Cov.: 33 AF XY: 0.00492 AC XY: 3577 AN XY: 727076

Gnomad4 AFR exome AF: 0.000836

Gnomad4 AMR exome AF: 0.00233

Gnomad4 ASJ exome AF: 0.000803

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000974

Gnomad4 FIN exome AF: 0.00485

Gnomad4 NFE exome AF: 0.00601

Gnomad4 OTH exome AF: 0.00444

GnomAD4 genome AF: 0.00394 AC: 599 AN: 152108 Hom.: 2 Cov.: 32 AF XY: 0.00361 AC XY: 268 AN XY: 74332

Gnomad4 AFR AF: 0.000843

Gnomad4 AMR AF: 0.00419

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00530

Gnomad4 NFE AF: 0.00606

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00502 Hom.: 2

Bravo AF: 0.00429

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00583

EpiControl AF: 0.00492

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 21, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	0.20
Dann	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00027
dbscSNV1_RF	Benign	0.0020
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: rs183549619; hg19: chr12-6882083; COSMIC: COSV52567488; COSMIC: COSV52567488;