rs781908326

Variant names:

• chrX-153872214-C-A
• rs781908326
• NM_001278116.2:c.338G>T

Your query was ambiguous. Multiple possible variants found:

• chrX-153872214-C-A
• chrX-153872214-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001278116.2(L1CAM):​c.338G>T​(p.Arg113Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R113H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: L1CAM NM_001278116.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.127
• Publications: 1 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: Genomics England PanelApp, Orphanet, G2P
• 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

ENSG00000284987 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L1CAM	NM_001278116.2	c.338G>T	p.Arg113Leu	missense_variant	Exon 5 of 29	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.338G>T	p.Arg113Leu	missense_variant	Exon 4 of 28		NP_000416.1
L1CAM	NM_024003.3	c.338G>T	p.Arg113Leu	missense_variant	Exon 4 of 27		NP_076493.1
L1CAM	NM_001143963.2	c.323G>T	p.Arg108Leu	missense_variant	Exon 3 of 26		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7	c.338G>T	p.Arg113Leu	missense_variant	Exon 5 of 29	5	NM_001278116.2	ENSP00000359077.1
ENSG00000284987	ENST00000646191.1	n.*380G>T		downstream_gene_variant				ENSP00000493873.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD2 exomes AF: 0.00000545 AC: 1 AN: 183388 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000722

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.11e-7 AC: 1 AN: 1097343 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 1 AN XY: 362719

African (AFR) AF: 0.00 AC: 0 AN: 26393

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19382

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54127

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40511

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841320

Other (OTH) AF: 0.00 AC: 0 AN: 46065

GnomAD4 genome Cov.: 21

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	.;D;.;.;T;T
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.92	D;D;.;D;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.49	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	.;L;.;L;.;.
PhyloP100		0.13
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-4.4	D;D;D;D;D;D
REVEL	Benign	0.18
Sift	Uncertain	0.0020	D;D;D;D;D;D
Sift4G	Uncertain	0.019	D;D;D;D;.;.
Polyphen		1.0, 0.95	.;D;.;P;.;.
Vest4		0.61
MutPred		0.66		.;Loss of MoRF binding (P = 0.0083);.;Loss of MoRF binding (P = 0.0083);Loss of MoRF binding (P = 0.0083);.;
MVP		0.59
MPC		1.7
ClinPred		0.86	D
GERP RS		5.0
Varity_R		0.76
gMVP		0.98
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs781908326; hg19: chrX-153137669;