rs3743481

Variant names:

• chr15-77614803-G-A
• rs3743481
• NM_032808.7:c.1104C>T
• LINGO1 p.Ser368Ser

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.1104C>T​(p.Ser368Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.403 in 1,608,936 control chromosomes in the GnomAD database, including 134,990 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15345 hom., cov: 33)
  • Exomes 𝑓: 0.40 (119645 hom.)
• Consequence: LINGO1 NM_032808.7 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.50
• 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: AR, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

LOC105370906 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 15-77614803-G-A is Benign according to our data. Variant chr15-77614803-G-A is described in ClinVar as Benign. ClinVar VariationId is 1300108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.5 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.574 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032808.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LINGO1	NM_032808.7	MANE Select	c.1104C>T	p.Ser368Ser	synonymous	Exon 2 of 2	NP_116197.4
	LINGO1	NM_001301186.2		c.1086C>T	p.Ser362Ser	synonymous	Exon 6 of 6	NP_001288115.1	Q96FE5-2
	LINGO1	NM_001301187.2		c.1086C>T	p.Ser362Ser	synonymous	Exon 6 of 6	NP_001288116.1	Q96FE5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LINGO1	ENST00000355300.7	TSL:1 MANE Select	c.1104C>T	p.Ser368Ser	synonymous	Exon 2 of 2	ENSP00000347451.6	Q96FE5-1
	LINGO1	ENST00000561030.5	TSL:1	c.1086C>T	p.Ser362Ser	synonymous	Exon 4 of 4	ENSP00000453853.1	Q96FE5-2
	LINGO1	ENST00000557798.1	TSL:3	c.*141C>T		downstream_gene	N/A	ENSP00000453780.1	H0YMX3

Frequencies

GnomAD3 genomes AF: 0.442 AC: 67173 AN: 151988 Hom.: 15323 Cov.: 33

Gnomad AFR AF: 0.521

Gnomad AMI AF: 0.373

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.449

Gnomad EAS AF: 0.576

Gnomad SAS AF: 0.593

Gnomad FIN AF: 0.464

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.377

Gnomad OTH AF: 0.430

GnomAD2 exomes AF: 0.435 AC: 104385 AN: 240230 AF XY: 0.441

Gnomad AFR exome AF: 0.532

Gnomad AMR exome AF: 0.344

Gnomad ASJ exome AF: 0.445

Gnomad EAS exome AF: 0.590

Gnomad FIN exome AF: 0.452

Gnomad NFE exome AF: 0.382

Gnomad OTH exome AF: 0.422

GnomAD4 exome AF: 0.399 AC: 581507 AN: 1456830 Hom.: 119645 Cov.: 56 AF XY: 0.405 AC XY: 293322 AN XY: 724272

African (AFR) AF: 0.543 AC: 18148 AN: 33402

American (AMR) AF: 0.357 AC: 15693 AN: 43928

Ashkenazi Jewish (ASJ) AF: 0.450 AC: 11707 AN: 26042

East Asian (EAS) AF: 0.554 AC: 21875 AN: 39464

South Asian (SAS) AF: 0.577 AC: 49342 AN: 85482

European-Finnish (FIN) AF: 0.445 AC: 23610 AN: 53026

Middle Eastern (MID) AF: 0.507 AC: 2921 AN: 5758

European-Non Finnish (NFE) AF: 0.372 AC: 412794 AN: 1109552

Other (OTH) AF: 0.422 AC: 25417 AN: 60176

GnomAD4 genome AF: 0.442 AC: 67251 AN: 152106 Hom.: 15345 Cov.: 33 AF XY: 0.451 AC XY: 33520 AN XY: 74378

African (AFR) AF: 0.522 AC: 21645 AN: 41486

American (AMR) AF: 0.413 AC: 6316 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.449 AC: 1557 AN: 3466

East Asian (EAS) AF: 0.576 AC: 2972 AN: 5164

South Asian (SAS) AF: 0.592 AC: 2859 AN: 4826

European-Finnish (FIN) AF: 0.464 AC: 4918 AN: 10600

Middle Eastern (MID) AF: 0.463 AC: 136 AN: 294

European-Non Finnish (NFE) AF: 0.377 AC: 25600 AN: 67968

Other (OTH) AF: 0.431 AC: 908 AN: 2108

Alfa AF: 0.399 Hom.: 20379

Bravo AF: 0.437

Asia WGS AF: 0.546 AC: 1895 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Intellectual disability, autosomal recessive 64 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.3
DANN	Benign	0.76
PhyloP100		2.5
Mutation Taster		=99/1	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3743481;

hg19: chr15-77907145;

COSMIC: COSV62437034;

COSMIC: COSV62437034;