rs781830365

Positions:

• chrX-153869600-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1 PM2 BP4 BP6_Moderate

The NM_001278116.2(L1CAM):​c.1187C>A​(p.Pro396His) 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. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: L1CAM NM_001278116.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.46

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 1 ACMG points.

• PM1: In a domain Ig-like C2-type 4 (size 87) in uniprot entity L1CAM_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_001278116.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29914147).
• BP6: Variant X-153869600-G-T is Benign according to our data. Variant chrX-153869600-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 435688.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
L1CAM	NM_001278116.2	c.1187C>A	p.Pro396His	missense_variant	11/29	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.1187C>A	p.Pro396His	missense_variant	10/28		NP_000416.1
L1CAM	NM_024003.3	c.1187C>A	p.Pro396His	missense_variant	10/27		NP_076493.1
L1CAM	NM_001143963.2	c.1172C>A	p.Pro391His	missense_variant	9/26		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7	c.1187C>A	p.Pro396His	missense_variant	11/29	5	NM_001278116.2	ENSP00000359077	A1
L1CAM	ENST00000361699.8	c.1187C>A	p.Pro396His	missense_variant	10/27	1		ENSP00000355380	P4
L1CAM	ENST00000361981.7	c.1172C>A	p.Pro391His	missense_variant	9/26	1		ENSP00000354712	A1
L1CAM	ENST00000370055.5	c.1172C>A	p.Pro391His	missense_variant	10/27	5		ENSP00000359072	A1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD3 exomes AF: 0.00000567 AC: 1 AN: 176356 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 62506

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000127

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 24

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 08, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	.;T;.;.
FATHMM_MKL	Benign	0.50	D
LIST_S2	Uncertain	0.88	D;D;.;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Benign	0.30	T;T;T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.9	.;L;.;L
MutationTaster	Benign	0.98	N;N;N;N;N;N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.5	N;N;N;N
REVEL	Uncertain	0.36
Sift	Uncertain	0.019	D;D;D;D
Sift4G	Benign	0.29	T;T;T;T
Polyphen		0.23, 0.28	.;B;.;B
Vest4		0.32
MutPred		0.41		.;Gain of catalytic residue at P396 (P = 0.0593);.;Gain of catalytic residue at P396 (P = 0.0593);
MVP		0.83
MPC		1.6
ClinPred		0.34	T
GERP RS		4.7
Varity_R		0.24
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs781830365; hg19: chrX-153135055;