19-2290612-C-A

Position:

• chr19-2290612-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001101391.3(LINGO3):​c.1165G>T​(p.Ala389Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,437,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: LINGO3 NM_001101391.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.04

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1352644).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LINGO3	NM_001101391.3	c.1165G>T	p.Ala389Ser	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.1165G>T	p.Ala389Ser	missense_variant	2/2		NM_001101391.3	ENSP00000513689.1
ENSG00000273734	ENST00000621615.1	n.146+20868C>A		intron_variant		2		ENSP00000481965.1
LINGO3	ENST00000585527.1	c.1165G>T	p.Ala389Ser	missense_variant	1/1	6		ENSP00000467753.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1437776 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 714394

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: 9.05e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Feb 27, 2024

The c.1165G>T (p.A389S) alteration is located in exon 2 (coding exon 1) of the LINGO3 gene. This alteration results from a G to T substitution at nucleotide position 1165, causing the alanine (A) at amino acid position 389 to be replaced by a serine (S). 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	0.086
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.000064	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.40
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.47	T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.035	N
PrimateAI	Uncertain	0.78	T
Sift4G	Benign	0.81	T
Polyphen		0.052	B
Vest4		0.056
MutPred		0.31		Gain of phosphorylation at A389 (P = 0.0322);
MVP		0.067
ClinPred		0.18	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.50

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: rs771157725; hg19: chr19-2290611;