rs7052999

Variant names:

• chrX-153863583-G-A
• rs7052999
• NM_001278116.2:c.3458-34C>T

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.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:3
• Conservation: PhyloP100: -0.0700
• Publications: 1 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=-0.9).
• 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.
• 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 rank	MANE	Protein	UniProt
L1CAM	NM_001278116.2	c.3458-34C>T		intron_variant	Intron 26 of 28	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.3458-34C>T		intron_variant	Intron 25 of 27		NP_000416.1
L1CAM	NM_024003.3	c.3458-34C>T		intron_variant	Intron 25 of 26		NP_076493.1
L1CAM	NM_001143963.2	c.3443-34C>T		intron_variant	Intron 24 of 25		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7	c.3458-34C>T		intron_variant	Intron 26 of 28	5	NM_001278116.2	ENSP00000359077.1

Frequencies

GnomAD3 genomes AF: 0.0519 AC: 5805 AN: 111782 Hom.: 192 Cov.: 23

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

GnomAD2 exomes AF: 0.0451 AC: 7072 AN: 156915 AF XY: 0.0406

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 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

African (AFR) AF: 0.119 AC: 2992 AN: 25212

American (AMR) AF: 0.0926 AC: 3123 AN: 33715

Ashkenazi Jewish (ASJ) AF: 0.0217 AC: 410 AN: 18907

East Asian (EAS) AF: 0.0303 AC: 891 AN: 29387

South Asian (SAS) AF: 0.0507 AC: 2613 AN: 51545

European-Finnish (FIN) AF: 0.00973 AC: 380 AN: 39064

Middle Eastern (MID) AF: 0.0691 AC: 269 AN: 3893

European-Non Finnish (NFE) AF: 0.0257 AC: 20333 AN: 790761

Other (OTH) AF: 0.0352 AC: 1548 AN: 43937

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

African (AFR) AF: 0.115 AC: 3531 AN: 30712

American (AMR) AF: 0.0571 AC: 609 AN: 10666

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 52 AN: 2649

East Asian (EAS) AF: 0.0282 AC: 100 AN: 3545

South Asian (SAS) AF: 0.0520 AC: 140 AN: 2693

European-Finnish (FIN) AF: 0.0107 AC: 66 AN: 6152

Middle Eastern (MID) AF: 0.0419 AC: 9 AN: 215

European-Non Finnish (NFE) AF: 0.0229 AC: 1214 AN: 53000

Other (OTH) AF: 0.0525 AC: 80 AN: 1524

Alfa AF: 0.0620 Hom.: 1067

Bravo AF: 0.0604

ClinVar

Significance: 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: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: 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	-0.90
CADD	Benign	0.027
DANN	Benign	0.58
PhyloP100		-0.070
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: rs7052999; hg19: chrX-153129038;