rs202082978

Variant names:

• chrX-153864852-G-A
• rs202082978
• NM_001278116.2:c.3015C>T
• L1CAM p.Ile1005Ile

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 2 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: G2P, Genomics England PanelApp, Orphanet
• 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• X-linked complicated spastic paraplegia type 1

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 195651.
• 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 the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 21 XL gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	L1CAM	NM_001278116.2	MANE Select	c.3015C>T	p.Ile1005Ile	synonymous	Exon 23 of 29	NP_001265045.1	P32004-1
	L1CAM	NM_000425.5		c.3015C>T	p.Ile1005Ile	synonymous	Exon 22 of 28	NP_000416.1	P32004-1
	L1CAM	NM_024003.3		c.3015C>T	p.Ile1005Ile	synonymous	Exon 22 of 27	NP_076493.1	P32004-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	L1CAM	ENST00000370060.7	TSL:5 MANE Select	c.3015C>T	p.Ile1005Ile	synonymous	Exon 23 of 29	ENSP00000359077.1	P32004-1
	L1CAM	ENST00000361699.8	TSL:1	c.3015C>T	p.Ile1005Ile	synonymous	Exon 22 of 27	ENSP00000355380.4	P32004-2
	L1CAM	ENST00000361981.7	TSL:1	c.3000C>T	p.Ile1000Ile	synonymous	Exon 21 of 26	ENSP00000354712.3	P32004-3

Frequencies

GnomAD3 genomes AF: 0.000372 AC: 42 AN: 112971 Hom.: 1 Cov.: 24

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

GnomAD2 exomes AF: 0.00179 AC: 328 AN: 183447 AF XY: 0.00298

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 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

African (AFR) AF: 0.000189 AC: 5 AN: 26402

American (AMR) AF: 0.00 AC: 0 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.0168 AC: 912 AN: 54146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40506

Middle Eastern (MID) AF: 0.000725 AC: 3 AN: 4137

European-Non Finnish (NFE) AF: 0.0000107 AC: 9 AN: 842088

Other (OTH) AF: 0.00106 AC: 49 AN: 46096

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

African (AFR) AF: 0.0000320 AC: 1 AN: 31217

American (AMR) AF: 0.00 AC: 0 AN: 10818

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2656

East Asian (EAS) AF: 0.00 AC: 0 AN: 3573

South Asian (SAS) AF: 0.0142 AC: 39 AN: 2749

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6301

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53252

Other (OTH) AF: 0.00 AC: 0 AN: 1553

Alfa AF: 0.000214 Hom.: 1

Bravo AF: 0.000121

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not specified (2)
-	-	1	not provided (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.30
DANN	Benign	0.71
PhyloP100		-1.4
PromoterAI		0.0012	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs202082978;

hg19: chrX-153130307;