X-153862460-C-G

Variant names:

• chrX-153862460-C-G
• rs150098621
• NM_001278116.2:c.*203G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001278116.2(L1CAM):​c.*203G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00547 in 382,774 control chromosomes in the GnomAD database, including 43 homozygotes. There are 570 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 0.014 (33 hom., 412 hem., cov: 23)
  • Exomes 𝑓: 0.0021 (10 hom. 158 hem.)
• Consequence: L1CAM NM_001278116.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.28
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant X-153862460-C-G is Benign according to our data. Variant chrX-153862460-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1219357.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0136 (1526/112605) while in subpopulation AFR AF = 0.0464 (1441/31060). AF 95% confidence interval is 0.0444. There are 33 homozygotes in GnomAd4. There are 412 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L1CAM	NM_001278116.2	c.*203G>C		3_prime_UTR_variant	Exon 29 of 29	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.*203G>C		3_prime_UTR_variant	Exon 28 of 28		NP_000416.1
L1CAM	NM_024003.3	c.*203G>C		3_prime_UTR_variant	Exon 27 of 27		NP_076493.1
L1CAM	NM_001143963.2	c.*203G>C		3_prime_UTR_variant	Exon 26 of 26		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7	c.*203G>C		3_prime_UTR_variant	Exon 29 of 29	5	NM_001278116.2	ENSP00000359077.1

Frequencies

GnomAD3 genomes AF: 0.0135 AC: 1523 AN: 112554 Hom.: 33 Cov.: 23

Gnomad AFR AF: 0.0464

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.000263

Gnomad OTH AF: 0.00859

GnomAD4 exome AF: 0.00210 AC: 567 AN: 270169 Hom.: 10 Cov.: 3 AF XY: 0.00192 AC XY: 158 AN XY: 82173

African (AFR) AF: 0.0446 AC: 385 AN: 8636

American (AMR) AF: 0.00435 AC: 52 AN: 11957

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8657

East Asian (EAS) AF: 0.00 AC: 0 AN: 21552

South Asian (SAS) AF: 0.00 AC: 0 AN: 12452

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20609

Middle Eastern (MID) AF: 0.00169 AC: 2 AN: 1180

European-Non Finnish (NFE) AF: 0.000214 AC: 36 AN: 168093

Other (OTH) AF: 0.00540 AC: 92 AN: 17033

GnomAD4 genome AF: 0.0136 AC: 1526 AN: 112605 Hom.: 33 Cov.: 23 AF XY: 0.0118 AC XY: 412 AN XY: 34777

African (AFR) AF: 0.0464 AC: 1441 AN: 31060

American (AMR) AF: 0.00530 AC: 57 AN: 10762

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3559

South Asian (SAS) AF: 0.00 AC: 0 AN: 2732

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6216

Middle Eastern (MID) AF: 0.00459 AC: 1 AN: 218

European-Non Finnish (NFE) AF: 0.000263 AC: 14 AN: 53202

Other (OTH) AF: 0.00849 AC: 13 AN: 1531

Alfa AF: 0.00947 Hom.: 28

Bravo AF: 0.0157

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 09, 2018

GeneDx

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	-0.83
CADD	Benign	0.26
DANN	Benign	0.47
PhyloP100		-1.3
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: rs150098621; hg19: chrX-153127915;