rs1557092782

Positions:

• chrX-153870490-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_001278116.2(L1CAM):​c.704T>C​(p.Met235Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: L1CAM NM_001278116.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.14

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.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant X-153870490-A-G is Benign according to our data. Variant chrX-153870490-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 432023.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
L1CAM	NM_001278116.2	c.704T>C	p.Met235Thr	missense_variant	8/29	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.704T>C	p.Met235Thr	missense_variant	7/28		NP_000416.1
L1CAM	NM_024003.3	c.704T>C	p.Met235Thr	missense_variant	7/27		NP_076493.1
L1CAM	NM_001143963.2	c.689T>C	p.Met230Thr	missense_variant	6/26		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7	c.704T>C	p.Met235Thr	missense_variant	8/29	5	NM_001278116.2	ENSP00000359077.1
L1CAM	ENST00000361699.8	c.704T>C	p.Met235Thr	missense_variant	7/27	1		ENSP00000355380.4
L1CAM	ENST00000361981.7	c.689T>C	p.Met230Thr	missense_variant	6/26	1		ENSP00000354712.3
L1CAM	ENST00000370055.5	c.689T>C	p.Met230Thr	missense_variant	7/27	5		ENSP00000359072.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 23

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

X-linked hydrocephalus syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing;provider interpretation

Geisinger Autism and Developmental Medicine Institute, Geisinger Health System

Mar 06, 2018

This variant was identified in a 12 year old male with mild intellectual disability, motor speech disorder, adaptive deficits, dyspraxia, hypotonia, ADHD, bifid uvula, mild dolichocephaly, large ears, mild pectus excavatum, hypoplastic nipples, and slightly tapered fingers. This variant is absent from the gnomAD database. Computational prediction models are inconsistent. This variant has not been reported previously in the literature, to our knowledge. This variant was also present in the proband's healthy, adult brother, making it unlikely to be an explanation for the proband's history. Additionally, whole exome sequencing also identified two additional variants of uncertain significance. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 12, 2021

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	.;T;.;.
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.85	T;T;.;T
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.48	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.69	.;N;.;N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.21	N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.043	D;D;D;D
Sift4G	Uncertain	0.060	T;T;T;T
Polyphen		0.31, 0.58	.;B;.;P
Vest4		0.57
MutPred		0.39		.;Gain of disorder (P = 0.0627);.;Gain of disorder (P = 0.0627);
MVP		0.67
MPC		1.2
ClinPred		0.76	D
GERP RS		5.2
Varity_R		0.39
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1557092782; hg19: chrX-153135945;