19-2290789-G-A

Position:

• chr19-2290789-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001101391.3(LINGO3):​c.988C>T​(p.Leu330Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000548 in 1,460,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: LINGO3 NM_001101391.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.45

Genes affected

LINGO3 (HGNC:21206): (leucine rich repeat and Ig domain containing 3) Predicted to be integral component of membrane. Predicted to be active in extracellular matrix and extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000273734 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.896

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LINGO3	NM_001101391.3	c.988C>T	p.Leu330Phe	missense_variant	2/2	ENST00000698372.1	NP_001094861.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LINGO3	ENST00000698372.1	c.988C>T	p.Leu330Phe	missense_variant	2/2		NM_001101391.3	ENSP00000513689.1
ENSG00000273734	ENST00000621615.1	n.146+21045G>A		intron_variant		2		ENSP00000481965.1
LINGO3	ENST00000585527.1	c.988C>T	p.Leu330Phe	missense_variant	1/1	6		ENSP00000467753.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460408 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 726510

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: 0.00000720

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

Oct 06, 2021

The c.988C>T (p.L330F) alteration is located in exon 2 (coding exon 1) of the LINGO3 gene. This alteration results from a C to T substitution at nucleotide position 988, causing the leucine (L) at amino acid position 330 to be replaced by a phenylalanine (F). 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	Pathogenic	0.64
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.090	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.3	M
PrimateAI	Uncertain	0.70	T
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.70		Loss of disorder (P = 0.1424);
MVP		0.87
ClinPred		0.95	D
GERP RS		4.6
Varity_R		0.70
gMVP		0.82

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: rs2025510995; hg19: chr19-2290788; COSMIC: COSV68261545;