X-153862698-T-G

Variant names:

• chrX-153862698-T-G
• rs781854219
• NM_001278116.2:c.3739A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001278116.2(L1CAM):​c.3739A>C​(p.Thr1247Pro) 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. 12/21 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. T1247A) has been classified as Benign.

• Frequency: Genomes: not found (cov: 24)
• Consequence: L1CAM NM_001278116.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.887
• Publications: 2 publications found

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]

L1CAM Gene-Disease associations (from GenCC):

• L1 syndrome

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• X-linked hydrocephalus with stenosis of the aqueduct of Sylvius

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, G2P
• MASA syndrome

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• X-linked complicated corpus callosum dysgenesis

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• X-linked complicated spastic paraplegia type 1

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14747801).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L1CAM	NM_001278116.2	c.3739A>C	p.Thr1247Pro	missense_variant	Exon 29 of 29	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.3739A>C	p.Thr1247Pro	missense_variant	Exon 28 of 28		NP_000416.1
L1CAM	NM_024003.3	c.3727A>C	p.Thr1243Pro	missense_variant	Exon 27 of 27		NP_076493.1
L1CAM	NM_001143963.2	c.3712A>C	p.Thr1238Pro	missense_variant	Exon 26 of 26		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7	c.3739A>C	p.Thr1247Pro	missense_variant	Exon 29 of 29	5	NM_001278116.2	ENSP00000359077.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.0074	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	.;T;.;T;.
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.85	T;T;.;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.15	T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.70	.;N;.;.;.
PhyloP100		0.89
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.4	N;N;N;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.49	T;T;T;T;T
Sift4G	Benign	0.29	T;T;T;T;T
Polyphen		0.0020, 0.023	.;B;.;.;B
Vest4		0.14
MutPred		0.11		.;Loss of glycosylation at T1247 (P = 0.0256);.;.;.;
MVP		0.91
MPC		1.4
ClinPred		0.22	T
GERP RS		2.4
Varity_R		0.12
gMVP		0.48
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs781854219; hg19: chrX-153128153;