15-77615433-T-C

Variant names:

• chr15-77615433-T-C
• rs2271397
• NM_032808.7:c.474A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_032808.7(LINGO1):​c.474A>G​(p.Leu158Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.644 in 1,613,144 control chromosomes in the GnomAD database, including 337,142 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (32713 hom., cov: 33)
  • Exomes 𝑓: 0.64 (304429 hom.)
• Consequence: LINGO1 NM_032808.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.641
• Publications: 28 publications found

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 Gene-Disease associations (from GenCC):

• intellectual disability, autosomal recessive 64

  Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

LOC105370906 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 15-77615433-T-C is Benign according to our data. Variant chr15-77615433-T-C is described in ClinVar as Benign. ClinVar VariationId is 1270589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.641 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.778 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LINGO1	NM_032808.7	c.474A>G	p.Leu158Leu	synonymous_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.474A>G	p.Leu158Leu	synonymous_variant	Exon 2 of 2	1	NM_032808.7	ENSP00000347451.6

Frequencies

GnomAD3 genomes AF: 0.656 AC: 99424 AN: 151550 Hom.: 32682 Cov.: 33

Gnomad AFR AF: 0.671

Gnomad AMI AF: 0.630

Gnomad AMR AF: 0.653

Gnomad ASJ AF: 0.627

Gnomad EAS AF: 0.799

Gnomad SAS AF: 0.791

Gnomad FIN AF: 0.668

Gnomad MID AF: 0.649

Gnomad NFE AF: 0.628

Gnomad OTH AF: 0.652

GnomAD2 exomes AF: 0.668 AC: 166487 AN: 249156 AF XY: 0.675

Gnomad AFR exome AF: 0.672

Gnomad AMR exome AF: 0.623

Gnomad ASJ exome AF: 0.621

Gnomad EAS exome AF: 0.803

Gnomad FIN exome AF: 0.670

Gnomad NFE exome AF: 0.636

Gnomad OTH exome AF: 0.662

GnomAD4 exome AF: 0.643 AC: 939807 AN: 1461474 Hom.: 304429 Cov.: 63 AF XY: 0.648 AC XY: 471195 AN XY: 727034

African (AFR) AF: 0.685 AC: 22923 AN: 33478

American (AMR) AF: 0.627 AC: 28042 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.623 AC: 16290 AN: 26136

East Asian (EAS) AF: 0.805 AC: 31943 AN: 39696

South Asian (SAS) AF: 0.779 AC: 67168 AN: 86254

European-Finnish (FIN) AF: 0.665 AC: 35507 AN: 53370

Middle Eastern (MID) AF: 0.672 AC: 3877 AN: 5768

European-Non Finnish (NFE) AF: 0.625 AC: 694956 AN: 1111690

Other (OTH) AF: 0.648 AC: 39101 AN: 60362

GnomAD4 genome AF: 0.656 AC: 99507 AN: 151670 Hom.: 32713 Cov.: 33 AF XY: 0.662 AC XY: 49039 AN XY: 74128

African (AFR) AF: 0.671 AC: 27739 AN: 41350

American (AMR) AF: 0.653 AC: 9956 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.627 AC: 2173 AN: 3468

East Asian (EAS) AF: 0.799 AC: 4090 AN: 5122

South Asian (SAS) AF: 0.790 AC: 3800 AN: 4808

European-Finnish (FIN) AF: 0.668 AC: 7042 AN: 10548

Middle Eastern (MID) AF: 0.646 AC: 190 AN: 294

European-Non Finnish (NFE) AF: 0.628 AC: 42571 AN: 67816

Other (OTH) AF: 0.651 AC: 1373 AN: 2108

Alfa AF: 0.640 Hom.: 127052

Bravo AF: 0.653

Asia WGS AF: 0.738 AC: 2563 AN: 3476

EpiCase AF: 0.638

EpiControl AF: 0.637

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Sep 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Intellectual disability, autosomal recessive 64 Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	10
DANN	Benign	0.71
PhyloP100		0.64
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2271397; hg19: chr15-77907775; COSMIC: COSV108199607; COSMIC: COSV108199607;