X-153869568-G-C

Variant names:

• chrX-153869568-G-C
• rs782756293
• NM_001278116.2:c.1219C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001278116.2(L1CAM):​c.1219C>G​(p.Arg407Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000165 in 1,209,785 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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. R407H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000088 (0 hom., 0 hem., cov: 25)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: L1CAM NM_001278116.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.506
• 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: 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 5 uncertain in NM_001278116.2
• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	L1CAM	NM_001278116.2	MANE Select	c.1219C>G	p.Arg407Gly	missense	Exon 11 of 29	NP_001265045.1
	L1CAM	NM_000425.5		c.1219C>G	p.Arg407Gly	missense	Exon 10 of 28	NP_000416.1
	L1CAM	NM_024003.3		c.1219C>G	p.Arg407Gly	missense	Exon 10 of 27	NP_076493.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	L1CAM	ENST00000370060.7	TSL:5 MANE Select	c.1219C>G	p.Arg407Gly	missense	Exon 11 of 29	ENSP00000359077.1
	L1CAM	ENST00000361699.8	TSL:1	c.1219C>G	p.Arg407Gly	missense	Exon 10 of 27	ENSP00000355380.4
	L1CAM	ENST00000361981.7	TSL:1	c.1204C>G	p.Arg402Gly	missense	Exon 9 of 26	ENSP00000354712.3

Frequencies

GnomAD3 genomes AF: 0.00000885 AC: 1 AN: 113038 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00417

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096695 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 362357

African (AFR) AF: 0.00 AC: 0 AN: 26397

American (AMR) AF: 0.00 AC: 0 AN: 35106

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19213

East Asian (EAS) AF: 0.00 AC: 0 AN: 30185

South Asian (SAS) AF: 0.00 AC: 0 AN: 53697

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4126

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841618

Other (OTH) AF: 0.00 AC: 0 AN: 46027

GnomAD4 genome AF: 0.00000884 AC: 1 AN: 113090 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 35248

African (AFR) AF: 0.00 AC: 0 AN: 31221

American (AMR) AF: 0.00 AC: 0 AN: 10806

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2658

East Asian (EAS) AF: 0.00 AC: 0 AN: 3597

South Asian (SAS) AF: 0.00 AC: 0 AN: 2783

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6258

Middle Eastern (MID) AF: 0.00457 AC: 1 AN: 219

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53312

Other (OTH) AF: 0.00 AC: 0 AN: 1547

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.57	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Uncertain	0.0055	D
MutationAssessor	Benign	1.6	L
PhyloP100		0.51
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.74	N
REVEL	Uncertain	0.39
Sift	Benign	0.055	T
Sift4G	Benign	0.063	T
Polyphen		0.98	D
Vest4		0.27
MutPred		0.65		Loss of stability (P = 0.0112)
MVP		0.83
MPC		1.6
ClinPred		0.86	D
GERP RS		4.5
Varity_R		0.59
gMVP		0.94
Mutation Taster		=76/24	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: rs782756293; hg19: chrX-153135023;