15-77615442-G-C

Position:

• chr15-77615442-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_032808.7(LINGO1):​c.465C>G​(p.Ile155Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. I155I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LINGO1 NM_032808.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.436

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]

LOC105370906 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.756

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LINGO1	NM_032808.7	c.465C>G	p.Ile155Met	missense_variant	2/2	ENST00000355300.7
LOC105370906	XR_001751806.2	n.689-14843G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LINGO1	ENST00000355300.7	c.465C>G	p.Ile155Met	missense_variant	2/2	1	NM_032808.7	A1
LINGO1	ENST00000561030.5	c.447C>G	p.Ile149Met	missense_variant	4/4	1		P4
LINGO1	ENST00000557798.1	c.480C>G	p.Ile160Met	missense_variant	2/2	3
LINGO1	ENST00000561686.5	c.447C>G	p.Ile149Met	missense_variant	4/4	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 61

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;.;.;T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.78	T;T;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.76	D;D;D;D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.4	M;.;.;.
MutationTaster	Benign	2.6e-7	P;P
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.5	N;N;N;N
REVEL	Uncertain	0.49
Sift	Benign	0.041	D;D;D;T
Sift4G	Benign	0.096	T;T;T;.
Polyphen		0.99	D;.;.;.
Vest4		0.95
MutPred		0.61		Loss of methylation at K154 (P = 0.0279);.;.;.;
MVP		0.81
MPC		1.7
ClinPred		0.73	D
GERP RS		1.7
Varity_R		0.68
gMVP		0.69

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: rs2271398; hg19: chr15-77907784;