rs7052999

Positions:

• chrX-153863583-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001278116.2(L1CAM):​c.3458-34C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0334 in 1,148,254 control chromosomes in the GnomAD database, including 740 homozygotes. There are 11,876 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (190 hom., 1608 hem., cov: 23)
  • Exomes 𝑓: 0.031 (550 hom. 10268 hem.)
• Consequence: L1CAM NM_001278116.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0700

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant X-153863583-G-A is Benign according to our data. Variant chrX-153863583-G-A is described in ClinVar as [Benign]. Clinvar id is 256048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153863583-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.112 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
L1CAM	NM_001278116.2	c.3458-34C>T		intron_variant		ENST00000370060.7
L1CAM	NM_000425.5	c.3458-34C>T		intron_variant
L1CAM	NM_001143963.2	c.3443-34C>T		intron_variant
L1CAM	NM_024003.3	c.3458-34C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L1CAM	ENST00000370060.7	c.3458-34C>T		intron_variant		5	NM_001278116.2	A1

Frequencies

GnomAD3 genomes AF: 0.0519 AC: 5805 AN: 111782 Hom.: 192 Cov.: 23 AF XY: 0.0469 AC XY: 1594 AN XY: 34006

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.0310

Gnomad AMR AF: 0.0573

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.0284

Gnomad SAS AF: 0.0511

Gnomad FIN AF: 0.0107

Gnomad MID AF: 0.0468

Gnomad NFE AF: 0.0229

Gnomad OTH AF: 0.0532

GnomAD3 exomes AF: 0.0451 AC: 7072 AN: 156915 Hom.: 214 AF XY: 0.0406 AC XY: 1999 AN XY: 49265

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.0995

Gnomad ASJ exome AF: 0.0209

Gnomad EAS exome AF: 0.0278

Gnomad SAS exome AF: 0.0486

Gnomad FIN exome AF: 0.0103

Gnomad NFE exome AF: 0.0241

Gnomad OTH exome AF: 0.0429

GnomAD4 exome AF: 0.0314 AC: 32559 AN: 1036421 Hom.: 550 Cov.: 26 AF XY: 0.0329 AC XY: 10268 AN XY: 311787

Gnomad4 AFR exome AF: 0.119

Gnomad4 AMR exome AF: 0.0926

Gnomad4 ASJ exome AF: 0.0217

Gnomad4 EAS exome AF: 0.0303

Gnomad4 SAS exome AF: 0.0507

Gnomad4 FIN exome AF: 0.00973

Gnomad4 NFE exome AF: 0.0257

Gnomad4 OTH exome AF: 0.0352

GnomAD4 genome AF: 0.0521 AC: 5822 AN: 111833 Hom.: 190 Cov.: 23 AF XY: 0.0472 AC XY: 1608 AN XY: 34067

Gnomad4 AFR AF: 0.115

Gnomad4 AMR AF: 0.0571

Gnomad4 ASJ AF: 0.0196

Gnomad4 EAS AF: 0.0282

Gnomad4 SAS AF: 0.0520

Gnomad4 FIN AF: 0.0107

Gnomad4 NFE AF: 0.0229

Gnomad4 OTH AF: 0.0525

Alfa AF: 0.0385 Hom.: 280

Bravo AF: 0.0604

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.027
DANN	Benign	0.58

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: rs7052999; hg19: chrX-153129038;