X-153875809-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001278116.2(L1CAM):c.28C>G(p.Pro10Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,096,743 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. 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. P10S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: L1CAM NM_001278116.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.56

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22021094).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
L1CAM	NM_001278116.2	c.28C>G	p.Pro10Ala	missense_variant	2/29	ENST00000370060.7
L1CAM	NM_000425.5	c.28C>G	p.Pro10Ala	missense_variant	1/28
L1CAM	NM_024003.3	c.28C>G	p.Pro10Ala	missense_variant	1/27
L1CAM	NM_001143963.2	c.28C>G	p.Pro10Ala	missense_variant	1/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L1CAM	ENST00000370060.7	c.28C>G	p.Pro10Ala	missense_variant	2/29	5	NM_001278116.2	A1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1096743 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 362463

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: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	18
Dann	Benign	0.90
FATHMM_MKL	Benign	0.021	N
LIST_S2	Uncertain	0.89	D;D;.;D;D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N;N;N;N;.;.;.;.
MutationTaster	Benign	0.97	N;N;N;N;N;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.82	N;N;N;N;N;N;N;N
REVEL	Benign	0.10
Sift	Benign	0.036	D;D;D;D;T;T;T;D
Sift4G	Benign	0.99	T;T;T;T;.;.;D;.
Polyphen		0.0090, 0.047	.;B;.;B;.;.;.;.
Vest4		0.36
MutPred		0.53		Gain of MoRF binding (P = 0.0895);Gain of MoRF binding (P = 0.0895);Gain of MoRF binding (P = 0.0895);Gain of MoRF binding (P = 0.0895);Gain of MoRF binding (P = 0.0895);Gain of MoRF binding (P = 0.0895);Gain of MoRF binding (P = 0.0895);Gain of MoRF binding (P = 0.0895);
MVP		0.65
MPC		0.52
ClinPred		0.12	T
GERP RS		2.7
Varity_R		0.054
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs144605615; hg19: chrX-153141264;