rs191412165

Variant names:

• chrX-153869966-G-A
• rs191412165
• NM_001278116.2:c.992-32C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001278116.2(L1CAM):​c.992-32C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0052 in 1,207,689 control chromosomes in the GnomAD database, including 16 homozygotes. There are 2,181 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0037 (4 hom., 125 hem., cov: 24)
  • Exomes 𝑓: 0.0054 (12 hom. 2056 hem.)
• Consequence: L1CAM NM_001278116.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.20
• 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: 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant X-153869966-G-A is Benign according to our data. Variant chrX-153869966-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00372 (418/112306) while in subpopulation SAS AF = 0.0118 (32/2721). AF 95% confidence interval is 0.00856. There are 4 homozygotes in GnomAd4. There are 125 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L1CAM	NM_001278116.2	c.992-32C>T		intron_variant	Intron 9 of 28	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.992-32C>T		intron_variant	Intron 8 of 27		NP_000416.1
L1CAM	NM_024003.3	c.992-32C>T		intron_variant	Intron 8 of 26		NP_076493.1
L1CAM	NM_001143963.2	c.977-32C>T		intron_variant	Intron 7 of 25		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7	c.992-32C>T		intron_variant	Intron 9 of 28	5	NM_001278116.2	ENSP00000359077.1
L1CAM	ENST00000361699.8	c.992-32C>T		intron_variant	Intron 8 of 26	1		ENSP00000355380.4
L1CAM	ENST00000361981.7	c.977-32C>T		intron_variant	Intron 7 of 25	1		ENSP00000354712.3
L1CAM	ENST00000370055.5	c.977-32C>T		intron_variant	Intron 8 of 26	5		ENSP00000359072.1

Frequencies

GnomAD3 genomes AF: 0.00371 AC: 417 AN: 112257 Hom.: 4 Cov.: 24

Gnomad AFR AF: 0.000809

Gnomad AMI AF: 0.0131

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.000755

Gnomad EAS AF: 0.000284

Gnomad SAS AF: 0.0110

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00593

Gnomad OTH AF: 0.00461

GnomAD2 exomes AF: 0.00414 AC: 733 AN: 176872 AF XY: 0.00492

Gnomad AFR exome AF: 0.000645

Gnomad AMR exome AF: 0.00166

Gnomad ASJ exome AF: 0.000410

Gnomad EAS exome AF: 0.0000731

Gnomad FIN exome AF: 0.00213

Gnomad NFE exome AF: 0.00573

Gnomad OTH exome AF: 0.00454

GnomAD4 exome AF: 0.00536 AC: 5867 AN: 1095383 Hom.: 12 Cov.: 34 AF XY: 0.00569 AC XY: 2056 AN XY: 361407

African (AFR) AF: 0.000911 AC: 24 AN: 26351

American (AMR) AF: 0.00151 AC: 53 AN: 35113

Ashkenazi Jewish (ASJ) AF: 0.000569 AC: 11 AN: 19332

East Asian (EAS) AF: 0.00 AC: 0 AN: 30113

South Asian (SAS) AF: 0.00931 AC: 503 AN: 54019

European-Finnish (FIN) AF: 0.00219 AC: 87 AN: 39740

Middle Eastern (MID) AF: 0.0145 AC: 60 AN: 4130

European-Non Finnish (NFE) AF: 0.00586 AC: 4923 AN: 840628

Other (OTH) AF: 0.00448 AC: 206 AN: 45957

GnomAD4 genome AF: 0.00372 AC: 418 AN: 112306 Hom.: 4 Cov.: 24 AF XY: 0.00362 AC XY: 125 AN XY: 34484

African (AFR) AF: 0.000807 AC: 25 AN: 30976

American (AMR) AF: 0.00196 AC: 21 AN: 10736

Ashkenazi Jewish (ASJ) AF: 0.000755 AC: 2 AN: 2650

East Asian (EAS) AF: 0.000285 AC: 1 AN: 3514

South Asian (SAS) AF: 0.0118 AC: 32 AN: 2721

European-Finnish (FIN) AF: 0.00113 AC: 7 AN: 6177

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.00593 AC: 315 AN: 53092

Other (OTH) AF: 0.00390 AC: 6 AN: 1537

Alfa AF: 0.00418 Hom.: 30

Bravo AF: 0.00351

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.0040
DANN	Benign	0.66
PhyloP100		-3.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs191412165; hg19: chrX-153135421; COSMIC: COSV105918139; COSMIC: COSV105918139;