NM_001278116.2:c.704T>G

Variant names:

• chrX-153870490-A-C
• rs1557092782
• NM_001278116.2:c.704T>G

Variant summary

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

The NM_001278116.2(L1CAM):​c.704T>G​(p.Met235Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000913 in 1,095,474 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. M235T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: L1CAM NM_001278116.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.14
• 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 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.704T>G	p.Met235Arg	missense_variant	Exon 8 of 29	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.704T>G	p.Met235Arg	missense_variant	Exon 7 of 28		NP_000416.1
L1CAM	NM_024003.3	c.704T>G	p.Met235Arg	missense_variant	Exon 7 of 27		NP_076493.1
L1CAM	NM_001143963.2	c.689T>G	p.Met230Arg	missense_variant	Exon 6 of 26		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7	c.704T>G	p.Met235Arg	missense_variant	Exon 8 of 29	5	NM_001278116.2	ENSP00000359077.1
L1CAM	ENST00000361699.8	c.704T>G	p.Met235Arg	missense_variant	Exon 7 of 27	1		ENSP00000355380.4
L1CAM	ENST00000361981.7	c.689T>G	p.Met230Arg	missense_variant	Exon 6 of 26	1		ENSP00000354712.3
L1CAM	ENST00000370055.5	c.689T>G	p.Met230Arg	missense_variant	Exon 7 of 27	5		ENSP00000359072.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.13e-7 AC: 1 AN: 1095474 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 360868

African (AFR) AF: 0.00 AC: 0 AN: 26351

American (AMR) AF: 0.00 AC: 0 AN: 35189

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19372

East Asian (EAS) AF: 0.00 AC: 0 AN: 30196

South Asian (SAS) AF: 0.00 AC: 0 AN: 54046

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40499

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4132

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 839688

Other (OTH) AF: 0.00 AC: 0 AN: 46001

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	0.00041	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0	.;D;.;.
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.87	D;D;.;D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.71	D;D;D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.0	.;N;.;N
PhyloP100		5.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.6	D;D;D;D
REVEL	Benign	0.22
Sift	Benign	0.038	D;D;D;D
Sift4G	Uncertain	0.040	D;D;D;T
Vest4		0.71
ClinPred		0.96	D
GERP RS		5.2
Varity_R		0.84
gMVP		0.92
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.29		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1557092782; hg19: chrX-153135945;