15-77614082-C-T

Position:

chr15-77614082-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2PP2BP4_Strong

The NM_032808.7(LINGO1):c.1825G>A(p.Ala609Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000186 in 1,611,782 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000018 ( 1 hom. )

Consequence

LINGO1
NM_032808.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.05

Variant links:

Genes affected

LINGO1 (HGNC:21205): (leucine rich repeat and Ig domain containing 1) Predicted to enable epidermal growth factor receptor binding activity. Predicted to act upstream of or within generation of neurons and protein kinase B signaling. Predicted to be located in plasma membrane. Predicted to be active in extracellular matrix and extracellular space. Implicated in autosomal recessive non-syndromic intellectual disability and glaucoma. [provided by Alliance of Genome Resources, Apr 2022]

LINGO1 links:

LOC105370906 (HGNC:):

LOC105370906 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), LINGO1. . Gene score misZ 2.8006 (greater than the threshold 3.09). Trascript score misZ 3.5535 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, autosomal recessive 64.

BP4

Computational evidence support a benign effect (MetaRNN=0.047598153).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LINGO1	NM_032808.7 linkuse as main transcript	c.1825G>A	p.Ala609Thr	missense_variant	2/2	ENST00000355300.7	NP_116197.4
LOC105370906	XR_001751806.2 linkuse as main transcript	n.689-16203C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LINGO1	ENST00000355300.7 linkuse as main transcript	c.1825G>A	p.Ala609Thr	missense_variant	2/2	1	NM_032808.7	ENSP00000347451	A1	Q96FE5-1
LINGO1	ENST00000561030.5 linkuse as main transcript	c.1807G>A	p.Ala603Thr	missense_variant	4/4	1		ENSP00000453853	P4	Q96FE5-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000289

AC:

AN:

242306

Hom.:

AF XY:

0.0000303

AC XY:

AN XY:

131962

show subpopulations

Gnomad AFR exome

AF:

0.0000672

Gnomad AMR exome

AF:

0.000118

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000330

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000921

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1459494

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

725872

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000906

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000814

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000900

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152288

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000116

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.000251

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 08, 2024

The c.1825G>A (p.A609T) alteration is located in exon 2 (coding exon 2) of the LINGO1 gene. This alteration results from a G to A substitution at nucleotide position 1825, causing the alanine (A) at amino acid position 609 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Intellectual disability, autosomal recessive 64

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Apr 01, 2021

The homozygous missense c.1807G>A (p.Ala603Thr) variant identified in exon 6 (of 6) of the LINGO1 gene has not been reported in affected individuals in the literature. The variant has 0.00001971 allele frequency in the gnomAD(v3) database (3 out of 152170 heterozygous alleles, no homozygotes) suggesting it is not a common benign variant in the populations represented in that database. The variant affects a moderately conserved residue. In silico tools show conflicting predictions about potential pathogenicity of this variant. Based on the available evidence, the homozygous missense c.1807G>A (p.Ala603Thr) variant identified in the LINGO1 gene is reported as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.65

DEOGEN2

Benign

0.13

T;.

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.54

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.66

T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.048

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.14

N;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.43

N;N

REVEL

Benign

0.092

Sift

Benign

0.63

T;T

Sift4G

Benign

0.59

T;T

Polyphen

0.055

B;.

Vest4

0.075

MVP

0.23

MPC

0.78

ClinPred

0.021

GERP RS

3.5

Varity_R

0.054

gMVP

0.93

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over