X-153864035-GC-GCC

Variant names:

• chrX-153864035-G-GC
• rs782818719
• NM_001278116.2:c.3323-19dupG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001278116.2(L1CAM):​c.3323-19dupG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,209,960 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 503 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00077 (0 hom., 21 hem., cov: 24)
  • Exomes 𝑓: 0.0015 (0 hom. 482 hem.)
• Consequence: L1CAM NM_001278116.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.669
• 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: G2P, Orphanet, Genomics England PanelApp
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant X-153864035-G-GC is Benign according to our data. Variant chrX-153864035-G-GC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000769 (87/113151) while in subpopulation NFE AF = 0.00152 (81/53337). AF 95% confidence interval is 0.00125. There are 0 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.3323-19dupG		intron	N/A	NP_001265045.1	P32004-1
	L1CAM	NM_000425.5		c.3323-19dupG		intron	N/A	NP_000416.1	P32004-1
	L1CAM	NM_024003.3		c.3323-19dupG		intron	N/A	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.3323-19_3323-18insG		intron	N/A	ENSP00000359077.1	P32004-1
	L1CAM	ENST00000361699.8	TSL:1	c.3323-19_3323-18insG		intron	N/A	ENSP00000355380.4	P32004-2
	L1CAM	ENST00000361981.7	TSL:1	c.3308-19_3308-18insG		intron	N/A	ENSP00000354712.3	P32004-3

Frequencies

GnomAD3 genomes AF: 0.000769 AC: 87 AN: 113101 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000928

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000159

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00152

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000715 AC: 127 AN: 177537 AF XY: 0.000597

Gnomad AFR exome AF: 0.0000781

Gnomad AMR exome AF: 0.0000736

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000644

Gnomad NFE exome AF: 0.00154

Gnomad OTH exome AF: 0.000453

GnomAD4 exome AF: 0.00146 AC: 1598 AN: 1096809 Hom.: 0 Cov.: 32 AF XY: 0.00133 AC XY: 482 AN XY: 362343

African (AFR) AF: 0.0000758 AC: 2 AN: 26375

American (AMR) AF: 0.0000570 AC: 2 AN: 35117

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19370

East Asian (EAS) AF: 0.00 AC: 0 AN: 30169

South Asian (SAS) AF: 0.0000371 AC: 2 AN: 53936

European-Finnish (FIN) AF: 0.000198 AC: 8 AN: 40334

Middle Eastern (MID) AF: 0.00100 AC: 4 AN: 3999

European-Non Finnish (NFE) AF: 0.00182 AC: 1530 AN: 841511

Other (OTH) AF: 0.00109 AC: 50 AN: 45998

GnomAD4 genome AF: 0.000769 AC: 87 AN: 113151 Hom.: 0 Cov.: 24 AF XY: 0.000595 AC XY: 21 AN XY: 35295

African (AFR) AF: 0.000128 AC: 4 AN: 31270

American (AMR) AF: 0.0000927 AC: 1 AN: 10785

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2657

East Asian (EAS) AF: 0.00 AC: 0 AN: 3596

South Asian (SAS) AF: 0.00 AC: 0 AN: 2776

European-Finnish (FIN) AF: 0.000159 AC: 1 AN: 6283

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00152 AC: 81 AN: 53337

Other (OTH) AF: 0.00 AC: 0 AN: 1542

Alfa AF: 0.000868 Hom.: 6

Bravo AF: 0.000672

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	L1CAM-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.67
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

Other links and lift over

dbSNP: rs782818719; hg19: chrX-153129490;