15-77614501-T-C

Variant names:

• chr15-77614501-T-C
• rs868551107
• NM_032808.7:c.1406A>G

Variant summary

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

The NM_032808.7(LINGO1):​c.1406A>G​(p.Lys469Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,458,392 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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: 0.0000027 (1 hom.)
• Consequence: LINGO1 NM_032808.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24466333).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LINGO1	NM_032808.7	c.1406A>G	p.Lys469Arg	missense_variant	Exon 2 of 2	ENST00000355300.7	NP_116197.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LINGO1	ENST00000355300.7	c.1406A>G	p.Lys469Arg	missense_variant	Exon 2 of 2	1	NM_032808.7	ENSP00000347451.6
LINGO1	ENST00000561030.5	c.1388A>G	p.Lys463Arg	missense_variant	Exon 4 of 4	1		ENSP00000453853.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1458392 Hom.: 1 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 725618

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal recessive 64 Uncertain:1

Feb 11, 2020

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	0.00069	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	-0.10
Eigen_PC	Benign	0.090
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.34	N;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.18
Sift	Benign	0.23	T;T
Sift4G	Benign	0.30	T;T
Polyphen		0.011	B;.
Vest4		0.43
MutPred		0.55		Gain of methylation at K469 (P = 0.0335);.;
MVP		0.43
MPC		0.68
ClinPred		0.70	D
GERP RS		4.8
Varity_R		0.38
gMVP		0.45

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: rs868551107; hg19: chr15-77906843;