NM_001278116.2:c.3768A>G

Variant names:

• chrX-153862669-T-C
• rs782388898
• NM_001278116.2:c.3768A>G

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS1

The NM_001278116.2(L1CAM):​c.3768A>G​(p.Leu1256Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000549 in 1,092,602 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. L1256L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000055 (0 hom. 1 hem.)
• Consequence: L1CAM NM_001278116.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.679
• Publications: 0 publications found

Genes affected

L1CAM (HGNC:6470): (L1 cell adhesion molecule) The protein encoded by this gene is an axonal glycoprotein belonging to the immunoglobulin supergene family. The ectodomain, consisting of several immunoglobulin-like domains and fibronectin-like repeats (type III), is linked via a single transmembrane sequence to a conserved cytoplasmic domain. This cell adhesion molecule plays an important role in nervous system development, including neuronal migration and differentiation. Mutations in the gene cause X-linked neurological syndromes known as CRASH (corpus callosum hypoplasia, retardation, aphasia, spastic paraplegia and hydrocephalus). Alternative splicing of this gene results in multiple transcript variants, some of which include an alternate exon that is considered to be specific to neurons. [provided by RefSeq, May 2013]

L1CAM Gene-Disease associations (from GenCC):

• L1 syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• X-linked hydrocephalus with stenosis of the aqueduct of Sylvius

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp
• MASA syndrome

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• X-linked complicated corpus callosum dysgenesis

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• X-linked complicated spastic paraplegia type 1

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant X-153862669-T-C is Benign according to our data. Variant chrX-153862669-T-C is described in ClinVar as Benign. ClinVar VariationId is 2899524.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.679 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.00000549 (6/1092602) while in subpopulation EAS AF = 0.000199 (6/30176). AF 95% confidence interval is 0.0000861. There are 0 homozygotes in GnomAdExome4. There are 1 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278116.2. 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
	L1CAM	NM_001278116.2	MANE Select	c.3768A>G	p.Leu1256Leu	synonymous	Exon 29 of 29	NP_001265045.1	P32004-1
	L1CAM	NM_000425.5		c.3768A>G	p.Leu1256Leu	synonymous	Exon 28 of 28	NP_000416.1	P32004-1
	L1CAM	NM_024003.3		c.3756A>G	p.Leu1252Leu	synonymous	Exon 27 of 27	NP_076493.1	P32004-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	L1CAM	ENST00000370060.7	TSL:5 MANE Select	c.3768A>G	p.Leu1256Leu	synonymous	Exon 29 of 29	ENSP00000359077.1	P32004-1
	L1CAM	ENST00000361699.8	TSL:1	c.3756A>G	p.Leu1252Leu	synonymous	Exon 27 of 27	ENSP00000355380.4	P32004-2
	L1CAM	ENST00000361981.7	TSL:1	c.3741A>G	p.Leu1247Leu	synonymous	Exon 26 of 26	ENSP00000354712.3	P32004-3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.0000334 AC: 6 AN: 179800 AF XY: 0.0000463

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000433

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000549 AC: 6 AN: 1092602 Hom.: 0 Cov.: 29 AF XY: 0.00000279 AC XY: 1 AN XY: 358414

African (AFR) AF: 0.00 AC: 0 AN: 26304

American (AMR) AF: 0.00 AC: 0 AN: 35134

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19263

East Asian (EAS) AF: 0.000199 AC: 6 AN: 30176

South Asian (SAS) AF: 0.00 AC: 0 AN: 53837

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40470

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4111

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 837423

Other (OTH) AF: 0.00 AC: 0 AN: 45884

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	2.7
DANN	Benign	0.71
PhyloP100		-0.68
Mutation Taster		=100/0	polymorphism

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: rs782388898; hg19: chrX-153128124;