rs782420127

Positions:

• chrX-153864014-C-G
• chrX-153864014-C-T

Variant summary

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

The NM_001278116.2(L1CAM):​c.3326G>C​(p.Arg1109Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 25)
• Consequence: L1CAM NM_001278116.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.228

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=0.07872233).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
L1CAM	NM_001278116.2	c.3326G>C	p.Arg1109Pro	missense_variant	26/29	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.3326G>C	p.Arg1109Pro	missense_variant	25/28		NP_000416.1
L1CAM	NM_024003.3	c.3326G>C	p.Arg1109Pro	missense_variant	25/27		NP_076493.1
L1CAM	NM_001143963.2	c.3311G>C	p.Arg1104Pro	missense_variant	24/26		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7	c.3326G>C	p.Arg1109Pro	missense_variant	26/29	5	NM_001278116.2	ENSP00000359077	A1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 25

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	12
DANN	Benign	0.78
DEOGEN2	Benign	0.31	.;T;.;.
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.78	T;T;.;T
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.079	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;N;.;N
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.1	N;N;N;N
REVEL	Benign	0.056
Sift	Benign	0.22	T;T;T;T
Sift4G	Benign	0.25	T;T;T;T
Polyphen		0.0	.;B;.;B
Vest4		0.15
MutPred		0.49		.;Loss of catalytic residue at R1109 (P = 0.0054);.;Loss of catalytic residue at R1109 (P = 0.0054);
MVP		0.24
MPC		0.78
ClinPred		0.042	T
GERP RS		1.0
Varity_R		0.20
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs782420127; hg19: chrX-153129469;