rs782367931

chrX-153868561-C-GchrX-153868561-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001278116.2(L1CAM):c.1546G>C(p.Asp516His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D516N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: L1CAM NM_001278116.2 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.08

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
L1CAM	NM_001278116.2	c.1546G>C	p.Asp516His	missense_variant, splice_region_variant	13/29	ENST00000370060.7
L1CAM	NM_000425.5	c.1546G>C	p.Asp516His	missense_variant, splice_region_variant	12/28
L1CAM	NM_024003.3	c.1546G>C	p.Asp516His	missense_variant, splice_region_variant	12/27
L1CAM	NM_001143963.2	c.1531G>C	p.Asp511His	missense_variant, splice_region_variant	11/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L1CAM	ENST00000370060.7	c.1546G>C	p.Asp516His	missense_variant, splice_region_variant	13/29	5	NM_001278116.2	A1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1098197 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 363559

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

Alfa AF: 0.000111 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
Cadd	Pathogenic	34
Dann	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D;.;D
M_CAP	Pathogenic	0.68	D
MetaRNN	Uncertain	0.59	D;D;D;D
MetaSVM	Uncertain	-0.027	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.2	D;D;D;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.015	D;D;D;D
Polyphen		0.98, 0.95	.;D;.;P
Vest4		0.25
MutPred		0.58		.;Gain of MoRF binding (P = 0.0513);.;Gain of MoRF binding (P = 0.0513);
MVP		0.73
MPC		0.97
ClinPred		0.92	D
GERP RS		5.6
Varity_R		0.38
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.88		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.88		Position offset: 7
DS_DL_spliceai		0.64		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs782367931; hg19: chrX-153134016;