rs202082978

Positions:

• chrX-153864852-G-A

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.3015C>T​(p.Ile1005Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000841 in 1,211,194 control chromosomes in the GnomAD database, including 8 homozygotes. There are 582 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 0.00036 (1 hom., 21 hem., cov: 24)
  • Exomes 𝑓: 0.00089 (7 hom. 561 hem.)
• Consequence: L1CAM NM_001278116.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -1.44

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=-0.71).
• BP6: Variant X-153864852-G-A is Benign according to our data. Variant chrX-153864852-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 195651.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=2}.
• BP7: Synonymous conserved (PhyloP=-1.44 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000363 (41/113023) while in subpopulation SAS AF= 0.0142 (39/2749). AF 95% confidence interval is 0.0107. There are 1 homozygotes in gnomad4. There are 21 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 21 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
L1CAM	NM_001278116.2	c.3015C>T	p.Ile1005Ile	synonymous_variant	23/29	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.3015C>T	p.Ile1005Ile	synonymous_variant	22/28		NP_000416.1
L1CAM	NM_024003.3	c.3015C>T	p.Ile1005Ile	synonymous_variant	22/27		NP_076493.1
L1CAM	NM_001143963.2	c.3000C>T	p.Ile1000Ile	synonymous_variant	21/26		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7	c.3015C>T	p.Ile1005Ile	synonymous_variant	23/29	5	NM_001278116.2	ENSP00000359077.1
L1CAM	ENST00000361699.8	c.3015C>T	p.Ile1005Ile	synonymous_variant	22/27	1		ENSP00000355380.4
L1CAM	ENST00000361981.7	c.3000C>T	p.Ile1000Ile	synonymous_variant	21/26	1		ENSP00000354712.3
L1CAM	ENST00000370055.5	c.3000C>T	p.Ile1000Ile	synonymous_variant	22/27	5		ENSP00000359072.1

Frequencies

GnomAD3 genomes AF: 0.000372 AC: 42 AN: 112971 Hom.: 1 Cov.: 24 AF XY: 0.000598 AC XY: 21 AN XY: 35119

Gnomad AFR AF: 0.0000321

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00179 AC: 328 AN: 183447 Hom.: 3 AF XY: 0.00298 AC XY: 202 AN XY: 67891

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0170

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.000441

GnomAD4 exome AF: 0.000891 AC: 978 AN: 1098171 Hom.: 7 Cov.: 33 AF XY: 0.00154 AC XY: 561 AN XY: 363531

Gnomad4 AFR exome AF: 0.000189

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0168

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000107

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.000363 AC: 41 AN: 113023 Hom.: 1 Cov.: 24 AF XY: 0.000597 AC XY: 21 AN XY: 35181

Gnomad4 AFR AF: 0.0000320

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0142

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000214 Hom.: 1

Bravo AF: 0.000121

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 27, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 26, 2015	- -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 28, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 06, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.30
DANN	Benign	0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs202082978; hg19: chrX-153130307;