19-2290332-G-A

Position:

• chr19-2290332-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.1445C>T​(p.Ala482Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,396,490 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: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LINGO3 NM_001101391.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.56

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, 0.921

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LINGO3	NM_001101391.3	c.1445C>T	p.Ala482Val	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.1445C>T	p.Ala482Val	missense_variant	2/2		NM_001101391.3	ENSP00000513689.1
ENSG00000273734	ENST00000621615.1	n.146+20588G>A		intron_variant		2		ENSP00000481965.1
LINGO3	ENST00000585527.1	c.1445C>T	p.Ala482Val	missense_variant	1/1	6		ENSP00000467753.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1396490 Hom.: 0 Cov.: 33 AF XY: 0.00000145 AC XY: 1 AN XY: 691068

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: 0.00000184

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Jun 04, 2024

The c.1445C>T (p.A482V) 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 1445, causing the alanine (A) at amino acid position 482 to be replaced by a valine (V). 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	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.062	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	2.0	M
PrimateAI	Pathogenic	0.87	D
Sift4G	Benign	0.13	T
Polyphen		1.0	D
Vest4		0.85
MutPred		0.78		Loss of disorder (P = 0.103);
MVP		0.76
ClinPred		0.98	D
GERP RS		4.1
Varity_R		0.36
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-2290331;