rs143382184

Variant names:

• chrX-153867516-A-G
• rs143382184
• NM_001278116.2:c.1977T>C

Your query was ambiguous. Multiple possible variants found:

• chrX-153867516-A-G
• chrX-153867516-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001278116.2(L1CAM):​c.1977T>C​(p.Pro659Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00157 in 1,209,776 control chromosomes in the GnomAD database, including 24 homozygotes. There are 501 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0079 (9 hom., 243 hem., cov: 23)
  • Exomes 𝑓: 0.00092 (15 hom. 258 hem.)
• Consequence: L1CAM NM_001278116.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.79
• 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: 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.005).
• BP6: Variant X-153867516-A-G is Benign according to our data. Variant chrX-153867516-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 167233.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.79 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00791 (888/112310) while in subpopulation AFR AF = 0.0271 (839/30903). AF 95% confidence interval is 0.0256. There are 9 homozygotes in GnomAd4. There are 243 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.1977T>C	p.Pro659Pro	synonymous	Exon 17 of 29	NP_001265045.1	P32004-1
	L1CAM	NM_000425.5		c.1977T>C	p.Pro659Pro	synonymous	Exon 16 of 28	NP_000416.1	P32004-1
	L1CAM	NM_024003.3		c.1977T>C	p.Pro659Pro	synonymous	Exon 16 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.1977T>C	p.Pro659Pro	synonymous	Exon 17 of 29	ENSP00000359077.1	P32004-1
	L1CAM	ENST00000361699.8	TSL:1	c.1977T>C	p.Pro659Pro	synonymous	Exon 16 of 27	ENSP00000355380.4	P32004-2
	L1CAM	ENST00000361981.7	TSL:1	c.1962T>C	p.Pro654Pro	synonymous	Exon 15 of 26	ENSP00000354712.3	P32004-3

Frequencies

GnomAD3 genomes AF: 0.00791 AC: 888 AN: 112256 Hom.: 9 Cov.: 23

Gnomad AFR AF: 0.0272

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00206

Gnomad ASJ AF: 0.00567

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000940

Gnomad OTH AF: 0.00467

GnomAD2 exomes AF: 0.00243 AC: 446 AN: 183479 AF XY: 0.00175

Gnomad AFR exome AF: 0.0285

Gnomad AMR exome AF: 0.00109

Gnomad ASJ exome AF: 0.00321

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000854

Gnomad OTH exome AF: 0.00199

GnomAD4 exome AF: 0.000919 AC: 1009 AN: 1097466 Hom.: 15 Cov.: 31 AF XY: 0.000711 AC XY: 258 AN XY: 362824

African (AFR) AF: 0.0285 AC: 752 AN: 26388

American (AMR) AF: 0.00133 AC: 47 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 67 AN: 19383

East Asian (EAS) AF: 0.00 AC: 0 AN: 30203

South Asian (SAS) AF: 0.0000739 AC: 4 AN: 54133

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40517

Middle Eastern (MID) AF: 0.00145 AC: 6 AN: 4127

European-Non Finnish (NFE) AF: 0.0000297 AC: 25 AN: 841444

Other (OTH) AF: 0.00234 AC: 108 AN: 46064

GnomAD4 genome AF: 0.00791 AC: 888 AN: 112310 Hom.: 9 Cov.: 23 AF XY: 0.00705 AC XY: 243 AN XY: 34490

African (AFR) AF: 0.0271 AC: 839 AN: 30903

American (AMR) AF: 0.00206 AC: 22 AN: 10690

Ashkenazi Jewish (ASJ) AF: 0.00567 AC: 15 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3579

South Asian (SAS) AF: 0.00 AC: 0 AN: 2734

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6166

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.0000940 AC: 5 AN: 53171

Other (OTH) AF: 0.00461 AC: 7 AN: 1517

Alfa AF: 0.00224 Hom.: 14

Bravo AF: 0.00916

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	L1CAM-related disorder (1)
-	-	1	not provided (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.5
DANN	Benign	0.65
PhyloP100		-3.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs143382184; hg19: chrX-153132971;