chrX-153865714-C-A

Variant names:

• chrX-153865714-C-A
• rs149737236
• NM_001278116.2:c.2537G>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4 BP6 BS1 BS2

The NM_001278116.2(L1CAM):​c.2537G>T​(p.Arg846Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000166 in 1,199,816 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 73 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R846H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., 4 hem., cov: 24)
  • Exomes 𝑓: 0.00017 (0 hom. 69 hem.)
• Consequence: L1CAM NM_001278116.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 1.06
• Publications: 6 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.40040374).
• BP6: Variant X-153865714-C-A is Benign according to our data. Variant chrX-153865714-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 158794.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000134 (15/112314) while in subpopulation NFE AF = 0.000263 (14/53197). AF 95% confidence interval is 0.000159. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 4 XL gene

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.2537G>T	p.Arg846Leu	missense	Exon 20 of 29	NP_001265045.1	P32004-1
	L1CAM	NM_000425.5		c.2537G>T	p.Arg846Leu	missense	Exon 19 of 28	NP_000416.1	P32004-1
	L1CAM	NM_024003.3		c.2537G>T	p.Arg846Leu	missense	Exon 19 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.2537G>T	p.Arg846Leu	missense	Exon 20 of 29	ENSP00000359077.1	P32004-1
	L1CAM	ENST00000361699.8	TSL:1	c.2537G>T	p.Arg846Leu	missense	Exon 19 of 27	ENSP00000355380.4	P32004-2
	L1CAM	ENST00000361981.7	TSL:1	c.2522G>T	p.Arg841Leu	missense	Exon 18 of 26	ENSP00000354712.3	P32004-3

Frequencies

GnomAD3 genomes AF: 0.000134 AC: 15 AN: 112314 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000263

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000109 AC: 20 AN: 183447 AF XY: 0.0000736

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 FIN exome AF: 0.000187

Gnomad NFE exome AF: 0.000208

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000169 AC: 184 AN: 1087502 Hom.: 0 Cov.: 30 AF XY: 0.000195 AC XY: 69 AN XY: 353654

African (AFR) AF: 0.0000763 AC: 2 AN: 26197

American (AMR) AF: 0.00 AC: 0 AN: 35201

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19317

East Asian (EAS) AF: 0.00 AC: 0 AN: 30173

South Asian (SAS) AF: 0.00 AC: 0 AN: 53879

European-Finnish (FIN) AF: 0.0000988 AC: 4 AN: 40485

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4111

European-Non Finnish (NFE) AF: 0.000209 AC: 174 AN: 832364

Other (OTH) AF: 0.0000874 AC: 4 AN: 45775

GnomAD4 genome AF: 0.000134 AC: 15 AN: 112314 Hom.: 0 Cov.: 24 AF XY: 0.000116 AC XY: 4 AN XY: 34474

African (AFR) AF: 0.0000324 AC: 1 AN: 30892

American (AMR) AF: 0.00 AC: 0 AN: 10712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2660

East Asian (EAS) AF: 0.00 AC: 0 AN: 3550

South Asian (SAS) AF: 0.00 AC: 0 AN: 2735

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6141

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.000263 AC: 14 AN: 53197

Other (OTH) AF: 0.00 AC: 0 AN: 1508

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.000106

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000743 AC: 5

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.00

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary spastic paraplegia (1)
-	1	-	Hydrocephalus due to aqueductal stenosis (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.1
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.4	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.21	T
Polyphen		0.013	B
Vest4		0.44
MVP		0.84
MPC		1.6
ClinPred		0.17	T
GERP RS		3.6
Varity_R		0.20
gMVP		0.77
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs149737236; hg19: chrX-153131169;