rs112841948

Variant names:

• chrX-153868962-G-A
• rs112841948
• NM_001278116.2:c.1268-10C>T

Your query was ambiguous. Multiple possible variants found:

• chrX-153868962-G-A
• chrX-153868962-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001278116.2(L1CAM):​c.1268-10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00704 in 1,178,979 control chromosomes in the GnomAD database, including 405 homozygotes. There are 2,187 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (200 hom., 1090 hem., cov: 24)
  • Exomes 𝑓: 0.0040 (205 hom. 1097 hem.)
• Consequence: L1CAM NM_001278116.2 intron
• Scores: Splicing: ADA: 0.00001525
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.344
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant X-153868962-G-A is Benign according to our data. Variant chrX-153868962-G-A is described in ClinVar as Benign. ClinVar VariationId is 92918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

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.1268-10C>T		intron	N/A	NP_001265045.1	P32004-1
	L1CAM	NM_000425.5		c.1268-10C>T		intron	N/A	NP_000416.1	P32004-1
	L1CAM	NM_024003.3		c.1268-10C>T		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.1268-10C>T		intron	N/A	ENSP00000359077.1	P32004-1
	L1CAM	ENST00000361699.8	TSL:1	c.1268-10C>T		intron	N/A	ENSP00000355380.4	P32004-2
	L1CAM	ENST00000361981.7	TSL:1	c.1253-10C>T		intron	N/A	ENSP00000354712.3	P32004-3

Frequencies

GnomAD3 genomes AF: 0.0357 AC: 4004 AN: 112252 Hom.: 200 Cov.: 24

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0148

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00110

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000263

Gnomad OTH AF: 0.0286

GnomAD2 exomes AF: 0.00968 AC: 1768 AN: 182676 AF XY: 0.00604

Gnomad AFR exome AF: 0.123

Gnomad AMR exome AF: 0.00427

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000111

Gnomad OTH exome AF: 0.00466

GnomAD4 exome AF: 0.00402 AC: 4288 AN: 1066673 Hom.: 205 Cov.: 28 AF XY: 0.00328 AC XY: 1097 AN XY: 334823

African (AFR) AF: 0.138 AC: 3583 AN: 25871

American (AMR) AF: 0.00569 AC: 200 AN: 35172

Ashkenazi Jewish (ASJ) AF: 0.000209 AC: 4 AN: 19182

East Asian (EAS) AF: 0.00 AC: 0 AN: 30107

South Asian (SAS) AF: 0.000243 AC: 13 AN: 53437

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40379

Middle Eastern (MID) AF: 0.00495 AC: 20 AN: 4042

European-Non Finnish (NFE) AF: 0.0000996 AC: 81 AN: 813444

Other (OTH) AF: 0.00859 AC: 387 AN: 45039

GnomAD4 genome AF: 0.0357 AC: 4010 AN: 112306 Hom.: 200 Cov.: 24 AF XY: 0.0316 AC XY: 1090 AN XY: 34472

African (AFR) AF: 0.123 AC: 3792 AN: 30816

American (AMR) AF: 0.0148 AC: 158 AN: 10690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2655

East Asian (EAS) AF: 0.00 AC: 0 AN: 3588

South Asian (SAS) AF: 0.00111 AC: 3 AN: 2713

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6213

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

European-Non Finnish (NFE) AF: 0.000263 AC: 14 AN: 53199

Other (OTH) AF: 0.0282 AC: 43 AN: 1523

Alfa AF: 0.0190 Hom.: 53

Bravo AF: 0.0411

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.9
DANN	Benign	0.40
PhyloP100		0.34
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000015
dbscSNV1_RF	Benign	0.010
SpliceAI score (max)		0.060		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: rs112841948; hg19: chrX-153134417;