rs757077698

Positions:

chr15-77615038-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP2PP3_ModeratePP5

The ENST00000355300.7(LINGO1):c.869G>A(p.Arg290His) variant causes a missense change. The variant allele was found at a frequency of 0.0000112 in 1,613,842 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R290C) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

LINGO1
ENST00000355300.7 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 6.16

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 Pathogenic. Variant got 10 ACMG points.

PM1

In a repeat LRR 9 (size 21) in uniprot entity LIGO1_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in ENST00000355300.7

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-77615039-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 1685925.Status of the report is criteria_provided_single_submitter, 1 stars.

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.842

PP5

Variant 15-77615038-C-T is Pathogenic according to our data. Variant chr15-77615038-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 560183.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr15-77615038-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LINGO1	NM_032808.7 linkuse as main transcript	c.869G>A	p.Arg290His	missense_variant	2/2	ENST00000355300.7	NP_116197.4
LOC105370906	XR_001751806.2 linkuse as main transcript	n.689-15247C>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.869G>A	p.Arg290His	missense_variant	2/2	1	NM_032808.7	ENSP00000347451	A1	Q96FE5-1
LINGO1	ENST00000561030.5 linkuse as main transcript	c.851G>A	p.Arg284His	missense_variant	4/4	1		ENSP00000453853	P4	Q96FE5-2
LINGO1	ENST00000557798.1 linkuse as main transcript	c.884G>A	p.Arg295His	missense_variant	2/2	3		ENSP00000453780

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461706

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727136

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Intellectual disability, autosomal recessive 64

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.33

T;.;.

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.91

D;D;D

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.84

D;D;D

MetaSVM

Uncertain

0.37

MutationAssessor

Uncertain

2.5

M;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-2.2

N;N;N

REVEL

Pathogenic

0.73

Sift

Benign

0.046

D;T;D

Sift4G

Benign

0.11

T;T;T

Polyphen

1.0

D;.;.

Vest4

0.63

MVP

0.75

MPC

2.0

ClinPred

0.94

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.50

gMVP

0.67

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