rs191412165

Positions:

• chrX-153869966-G-A

Variant summary

Our verdict is Benign. Variant got -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

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=-0.92).
• BP6: Variant X-153869966-G-A is Benign according to our data. Variant chrX-153869966-G-A is described in ClinVar as [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
L1CAM	NM_001278116.2	c.992-32C>T		intron_variant		ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.992-32C>T		intron_variant			NP_000416.1
L1CAM	NM_001143963.2	c.977-32C>T		intron_variant			NP_001137435.1
L1CAM	NM_024003.3	c.992-32C>T		intron_variant			NP_076493.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7	c.992-32C>T		intron_variant		5	NM_001278116.2	ENSP00000359077	A1
L1CAM	ENST00000361699.8	c.992-32C>T		intron_variant		1		ENSP00000355380	P4
L1CAM	ENST00000361981.7	c.977-32C>T		intron_variant		1		ENSP00000354712	A1
L1CAM	ENST00000370055.5	c.977-32C>T		intron_variant		5		ENSP00000359072	A1

Frequencies

GnomAD3 genomes AF: 0.00371 AC: 417 AN: 112257 Hom.: 4 Cov.: 24 AF XY: 0.00363 AC XY: 125 AN XY: 34425

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

GnomAD3 exomes AF: 0.00414 AC: 733 AN: 176872 Hom.: 1 AF XY: 0.00492 AC XY: 315 AN XY: 64078

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 SAS exome AF: 0.00948

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

Gnomad4 AFR exome AF: 0.000911

Gnomad4 AMR exome AF: 0.00151

Gnomad4 ASJ exome AF: 0.000569

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00931

Gnomad4 FIN exome AF: 0.00219

Gnomad4 NFE exome AF: 0.00586

Gnomad4 OTH exome AF: 0.00448

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

Gnomad4 AFR AF: 0.000807

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.000755

Gnomad4 EAS AF: 0.000285

Gnomad4 SAS AF: 0.0118

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00593

Gnomad4 OTH AF: 0.00390

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.0040
DANN	Benign	0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs191412165; hg19: chrX-153135421; COSMIC: COSV105918139; COSMIC: COSV105918139;