X-153862280-G-A

Variant names:

• chrX-153862280-G-A
• rs41311708
• NM_001278116.2:c.*383C>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.*383C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0456 in 172,551 control chromosomes in the GnomAD database, including 186 homozygotes. There are 1,913 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 0.042 (101 hom., 1234 hem., cov: 23)
  • Exomes 𝑓: 0.052 (85 hom. 679 hem.)
• Consequence: L1CAM NM_001278116.2 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0990
• Publications: 2 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=-0.84).
• BP6: Variant X-153862280-G-A is Benign according to our data. Variant chrX-153862280-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1344425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0652 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L1CAM	NM_001278116.2	c.*383C>T		3_prime_UTR_variant	Exon 29 of 29	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.*383C>T		3_prime_UTR_variant	Exon 28 of 28		NP_000416.1
L1CAM	NM_024003.3	c.*383C>T		3_prime_UTR_variant	Exon 27 of 27		NP_076493.1
L1CAM	NM_001143963.2	c.*383C>T		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.*383C>T		3_prime_UTR_variant	Exon 29 of 29	5	NM_001278116.2	ENSP00000359077.1
L1CAM	ENST00000361981.7	c.*383C>T		3_prime_UTR_variant	Exon 26 of 26	1		ENSP00000354712.3
L1CAM	ENST00000370055.5	c.*383C>T		3_prime_UTR_variant	Exon 27 of 27	5		ENSP00000359072.1
L1CAM	ENST00000370058.7	c.*383C>T		downstream_gene_variant		3		ENSP00000359075.3

Frequencies

GnomAD3 genomes AF: 0.0421 AC: 4691 AN: 111414 Hom.: 101 Cov.: 23

Gnomad AFR AF: 0.00958

Gnomad AMI AF: 0.0265

Gnomad AMR AF: 0.0340

Gnomad ASJ AF: 0.0351

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00412

Gnomad FIN AF: 0.0509

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0670

Gnomad OTH AF: 0.0430

GnomAD4 exome AF: 0.0521 AC: 3180 AN: 61087 Hom.: 85 Cov.: 0 AF XY: 0.0552 AC XY: 679 AN XY: 12295

African (AFR) AF: 0.00717 AC: 17 AN: 2371

American (AMR) AF: 0.0304 AC: 60 AN: 1971

Ashkenazi Jewish (ASJ) AF: 0.0396 AC: 91 AN: 2296

East Asian (EAS) AF: 0.00 AC: 0 AN: 5539

South Asian (SAS) AF: 0.00542 AC: 3 AN: 554

European-Finnish (FIN) AF: 0.0570 AC: 263 AN: 4612

Middle Eastern (MID) AF: 0.0221 AC: 6 AN: 272

European-Non Finnish (NFE) AF: 0.0648 AC: 2531 AN: 39074

Other (OTH) AF: 0.0475 AC: 209 AN: 4398

GnomAD4 genome AF: 0.0421 AC: 4692 AN: 111464 Hom.: 101 Cov.: 23 AF XY: 0.0366 AC XY: 1234 AN XY: 33700

African (AFR) AF: 0.00956 AC: 294 AN: 30768

American (AMR) AF: 0.0341 AC: 363 AN: 10652

Ashkenazi Jewish (ASJ) AF: 0.0351 AC: 93 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3487

South Asian (SAS) AF: 0.00414 AC: 11 AN: 2660

European-Finnish (FIN) AF: 0.0509 AC: 309 AN: 6076

Middle Eastern (MID) AF: 0.0140 AC: 3 AN: 215

European-Non Finnish (NFE) AF: 0.0670 AC: 3537 AN: 52770

Other (OTH) AF: 0.0424 AC: 64 AN: 1509

Alfa AF: 0.0536 Hom.: 289

Bravo AF: 0.0408

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia Benign:1

Jan 03, 2017

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.7
DANN	Benign	0.42
PhyloP100		0.099
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: rs41311708; hg19: chrX-153127735;