rs782367931

Variant names:

• chrX-153868561-C-T
• rs782367931
• NM_001278116.2:c.1546G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-153868561-C-T
• chrX-153868561-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001278116.2(L1CAM):​c.1546G>A​(p.Asp516Asn) variant causes a missense, splice region 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: L1CAM NM_001278116.2 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.08
• Publications: 0 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: G2P, Orphanet, Genomics England PanelApp
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278116.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	L1CAM	NM_001278116.2	MANE Select	c.1546G>A	p.Asp516Asn	missense splice_region	Exon 13 of 29	NP_001265045.1	P32004-1
	L1CAM	NM_000425.5		c.1546G>A	p.Asp516Asn	missense splice_region	Exon 12 of 28	NP_000416.1	P32004-1
	L1CAM	NM_024003.3		c.1546G>A	p.Asp516Asn	missense splice_region	Exon 12 of 27	NP_076493.1	P32004-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	L1CAM	ENST00000370060.7	TSL:5 MANE Select	c.1546G>A	p.Asp516Asn	missense splice_region	Exon 13 of 29	ENSP00000359077.1	P32004-1
	L1CAM	ENST00000361699.8	TSL:1	c.1546G>A	p.Asp516Asn	missense splice_region	Exon 12 of 27	ENSP00000355380.4	P32004-2
	L1CAM	ENST00000361981.7	TSL:1	c.1531G>A	p.Asp511Asn	missense splice_region	Exon 11 of 26	ENSP00000354712.3	P32004-3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Pathogenic	29
DANN	Benign	0.96
DEOGEN2	Uncertain	0.49	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.91	L
PhyloP100		3.1
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.31
Sift	Benign	0.50	T
Sift4G	Benign	0.47	T
Polyphen		0.011	B
Vest4		0.24
MutPred		0.52		Gain of MoRF binding (P = 0.0385)
MVP		0.73
MPC		0.53
ClinPred		0.37	T
GERP RS		5.6
PromoterAI		-0.13	Neutral
Varity_R		0.25
gMVP		0.58
Mutation Taster		=51/49	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.84		Position offset: 7
DS_DL_spliceai		0.48		Position offset: 0

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

Other links and lift over

dbSNP: rs782367931; hg19: chrX-153134016;