15-77614332-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_032808.7(LINGO1):c.1575C>T(p.Pro525=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00221 in 1,613,946 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (33 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (40 hom.)
• Consequence: LINGO1 NM_032808.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.89

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 15-77614332-G-A is Benign according to our data. Variant chr15-77614332-G-A is described in ClinVar as [Benign]. Clinvar id is 778558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.89 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0119 (1812/152346) while in subpopulation AFR AF= 0.0409 (1701/41582). AF 95% confidence interval is 0.0393. There are 33 homozygotes in gnomad4. There are 843 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LINGO1	NM_032808.7	c.1575C>T	p.Pro525=	synonymous_variant	2/2	ENST00000355300.7
LOC105370906	XR_001751806.2	n.689-15953G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LINGO1	ENST00000355300.7	c.1575C>T	p.Pro525=	synonymous_variant	2/2	1	NM_032808.7	A1
LINGO1	ENST00000561030.5	c.1557C>T	p.Pro519=	synonymous_variant	4/4	1		P4

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1805 AN: 152228 Hom.: 33 Cov.: 33

Gnomad AFR AF: 0.0409

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00956

GnomAD3 exomes AF: 0.00315 AC: 783 AN: 248782 Hom.: 16 AF XY: 0.00241 AC XY: 326 AN XY: 134994

Gnomad AFR exome AF: 0.0446

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000151

Gnomad OTH exome AF: 0.000827

GnomAD4 exome AF: 0.00120 AC: 1756 AN: 1461600 Hom.: 40 Cov.: 31 AF XY: 0.00103 AC XY: 752 AN XY: 727078

Gnomad4 AFR exome AF: 0.0428

Gnomad4 AMR exome AF: 0.00246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000576

Gnomad4 OTH exome AF: 0.00215

GnomAD4 genome AF: 0.0119 AC: 1812 AN: 152346 Hom.: 33 Cov.: 33 AF XY: 0.0113 AC XY: 843 AN XY: 74498

Gnomad4 AFR AF: 0.0409

Gnomad4 AMR AF: 0.00516

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00946

Alfa AF: 0.00715 Hom.: 12

Bravo AF: 0.0137

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

LINGO1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 06, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	11
Dann	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11853548; hg19: chr15-77906674;