rs28933683

chrX-153870854-G-AchrX-153870854-G-CchrX-153870854-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001278116.2(L1CAM):c.630C>T(p.His210=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000786 in 1,209,009 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 25 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., 7 hem., cov: 23)
  • Exomes 𝑓: 0.000060 (0 hom. 18 hem.)
• Consequence: L1CAM NM_001278116.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -2.29

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant X-153870854-G-A is Benign according to our data. Variant chrX-153870854-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 92933.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BP7: Synonymous conserved (PhyloP=-2.29 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000601 (66/1097525) while in subpopulation AFR AF= 0.0019 (50/26381). AF 95% confidence interval is 0.00148. There are 0 homozygotes in gnomad4_exome. There are 18 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
L1CAM	NM_001278116.2	c.630C>T	p.His210=	synonymous_variant	7/29	ENST00000370060.7
L1CAM	NM_000425.5	c.630C>T	p.His210=	synonymous_variant	6/28
L1CAM	NM_024003.3	c.630C>T	p.His210=	synonymous_variant	6/27
L1CAM	NM_001143963.2	c.615C>T	p.His205=	synonymous_variant	5/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L1CAM	ENST00000370060.7	c.630C>T	p.His210=	synonymous_variant	7/29	5	NM_001278116.2	A1
L1CAM	ENST00000361699.8	c.630C>T	p.His210=	synonymous_variant	6/27	1		P4
L1CAM	ENST00000361981.7	c.615C>T	p.His205=	synonymous_variant	5/26	1		A1
L1CAM	ENST00000370055.5	c.615C>T	p.His205=	synonymous_variant	6/27	5		A1

Frequencies

GnomAD3 genomes AF: 0.000260 AC: 29 AN: 111484 Hom.: 0 Cov.: 23 AF XY: 0.000208 AC XY: 7 AN XY: 33640

Gnomad AFR AF: 0.000947

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: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000927 AC: 17 AN: 183460 Hom.: 0 AF XY: 0.000103 AC XY: 7 AN XY: 67914

Gnomad AFR exome AF: 0.00122

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.0000601 AC: 66 AN: 1097525 Hom.: 0 Cov.: 33 AF XY: 0.0000496 AC XY: 18 AN XY: 362885

Gnomad4 AFR exome AF: 0.00190

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000107

Gnomad4 OTH exome AF: 0.000130

GnomAD4 genome AF: 0.000260 AC: 29 AN: 111484 Hom.: 0 Cov.: 23 AF XY: 0.000208 AC XY: 7 AN XY: 33640

Gnomad4 AFR AF: 0.000947

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000688 Hom.: 0

Bravo AF: 0.000253

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 06, 2013

- -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	0.12
Dann	Benign	0.56

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

Publications

LitVar

Other links and lift over

dbSNP: rs28933683; hg19: chrX-153136309;