rs35902890

Variant names:

• chrX-153865088-G-A
• rs35902890
• NM_001278116.2:c.2872C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-153865088-G-A
• chrX-153865088-G-C
• chrX-153865088-G-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001278116.2(L1CAM):​c.2872C>T​(p.Leu958Leu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000365 in 1,096,807 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000036 (0 hom. 0 hem.)
• Consequence: L1CAM NM_001278116.2 splice_region, synonymous
• Scores: Splicing: ADA: 0.0006176
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.58
• Publications: 5 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP7: Synonymous conserved (PhyloP=-3.59 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L1CAM	NM_001278116.2	c.2872C>T	p.Leu958Leu	splice_region_variant, synonymous_variant	Exon 22 of 29	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.2872C>T	p.Leu958Leu	splice_region_variant, synonymous_variant	Exon 21 of 28		NP_000416.1
L1CAM	NM_024003.3	c.2872C>T	p.Leu958Leu	splice_region_variant, synonymous_variant	Exon 21 of 27		NP_076493.1
L1CAM	NM_001143963.2	c.2857C>T	p.Leu953Leu	splice_region_variant, synonymous_variant	Exon 20 of 26		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7	c.2872C>T	p.Leu958Leu	splice_region_variant, synonymous_variant	Exon 22 of 29	5	NM_001278116.2	ENSP00000359077.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000560 AC: 1 AN: 178603 AF XY: 0.00

Gnomad AFR exome AF: 0.0000782

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000365 AC: 4 AN: 1096807 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 362641

African (AFR) AF: 0.0000379 AC: 1 AN: 26394

American (AMR) AF: 0.00 AC: 0 AN: 35173

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19352

East Asian (EAS) AF: 0.00 AC: 0 AN: 30190

South Asian (SAS) AF: 0.00 AC: 0 AN: 54109

European-Finnish (FIN) AF: 0.0000253 AC: 1 AN: 39511

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4131

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 841884

Other (OTH) AF: 0.00 AC: 0 AN: 46063

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 15

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.030
DANN	Benign	0.61
PhyloP100		-3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00062
dbscSNV1_RF	Benign	0.49
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: rs35902890; hg19: chrX-153130543; COSMIC: COSV62828552; COSMIC: COSV62828552;