NM_001278116.2:c.1124-6_1124-3dupGCAC

Variant names:

• chrX-153869665-T-TGTGC
• rs782713149
• NM_001278116.2:c.1124-6_1124-3dupGCAC

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001278116.2(L1CAM):​c.1124-6_1124-3dupGCAC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,093,138 control chromosomes in the GnomAD database, including 1 homozygotes. There are 23 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.000040 (1 hom. 23 hem.)
• Consequence: L1CAM NM_001278116.2 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:1
• Conservation: PhyloP100: 1.13

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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000403 (44/1093138) while in subpopulation SAS AF= 0.00079 (42/53170). AF 95% confidence interval is 0.0006. There are 1 homozygotes in gnomad4_exome. There are 23 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAdExome4 at 23 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L1CAM	NM_001278116.2	c.1124-6_1124-3dupGCAC		splice_region_variant, intron_variant	Intron 10 of 28	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.1124-6_1124-3dupGCAC		splice_region_variant, intron_variant	Intron 9 of 27		NP_000416.1
L1CAM	NM_024003.3	c.1124-6_1124-3dupGCAC		splice_region_variant, intron_variant	Intron 9 of 26		NP_076493.1
L1CAM	NM_001143963.2	c.1109-6_1109-3dupGCAC		splice_region_variant, intron_variant	Intron 8 of 25		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7	c.1124-3_1124-2insGCAC		splice_region_variant, intron_variant	Intron 10 of 28	5	NM_001278116.2	ENSP00000359077.1
L1CAM	ENST00000361699.8	c.1124-3_1124-2insGCAC		splice_region_variant, intron_variant	Intron 9 of 26	1		ENSP00000355380.4
L1CAM	ENST00000361981.7	c.1109-3_1109-2insGCAC		splice_region_variant, intron_variant	Intron 8 of 25	1		ENSP00000354712.3
L1CAM	ENST00000370055.5	c.1109-3_1109-2insGCAC		splice_region_variant, intron_variant	Intron 9 of 26	5		ENSP00000359072.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD3 exomes AF: 0.0000712 AC: 12 AN: 168449 Hom.: 1 AF XY: 0.0000888 AC XY: 5 AN XY: 56285

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000693

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000403 AC: 44 AN: 1093138 Hom.: 1 Cov.: 33 AF XY: 0.0000640 AC XY: 23 AN XY: 359410

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000790

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000436

GnomAD4 genome Cov.: 24

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

-

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

not specified Uncertain:1

May 04, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spastic paraplegia Benign:1

Jan 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs782713149; hg19: chrX-153135120;