chrX-153870474-C-T

Variant names:

• chrX-153870474-C-T
• rs35151382
• NM_001278116.2:c.720G>A

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.720G>A​(p.Pro240Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00198 in 1,209,913 control chromosomes in the GnomAD database, including 28 homozygotes. There are 706 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 0.0096 (10 hom., 307 hem., cov: 23)
  • Exomes 𝑓: 0.0012 (18 hom. 399 hem.)
• Consequence: L1CAM NM_001278116.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -4.38
• 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 (BayesDel_noAF=-0.74).
• BP6: Variant X-153870474-C-T is Benign according to our data. Variant chrX-153870474-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-4.38 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00964 (1084/112486) while in subpopulation AFR AF = 0.0332 (1031/31026). AF 95% confidence interval is 0.0315. There are 10 homozygotes in GnomAd4. There are 307 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 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.720G>A	p.Pro240Pro	synonymous	Exon 8 of 29	NP_001265045.1	P32004-1
	L1CAM	NM_000425.5		c.720G>A	p.Pro240Pro	synonymous	Exon 7 of 28	NP_000416.1	P32004-1
	L1CAM	NM_024003.3		c.720G>A	p.Pro240Pro	synonymous	Exon 7 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.720G>A	p.Pro240Pro	synonymous	Exon 8 of 29	ENSP00000359077.1	P32004-1
	L1CAM	ENST00000361699.8	TSL:1	c.720G>A	p.Pro240Pro	synonymous	Exon 7 of 27	ENSP00000355380.4	P32004-2
	L1CAM	ENST00000361981.7	TSL:1	c.705G>A	p.Pro235Pro	synonymous	Exon 6 of 26	ENSP00000354712.3	P32004-3

Frequencies

GnomAD3 genomes AF: 0.00961 AC: 1081 AN: 112432 Hom.: 10 Cov.: 23

Gnomad AFR AF: 0.0332

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00309

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000280

Gnomad SAS AF: 0.000733

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000940

Gnomad OTH AF: 0.00790

GnomAD2 exomes AF: 0.00276 AC: 503 AN: 182408 AF XY: 0.00211

Gnomad AFR exome AF: 0.0331

Gnomad AMR exome AF: 0.00131

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000433

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000861

Gnomad OTH exome AF: 0.00111

GnomAD4 exome AF: 0.00119 AC: 1311 AN: 1097427 Hom.: 18 Cov.: 32 AF XY: 0.00110 AC XY: 399 AN XY: 362807

African (AFR) AF: 0.0347 AC: 915 AN: 26380

American (AMR) AF: 0.00173 AC: 61 AN: 35201

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.000497 AC: 15 AN: 30203

South Asian (SAS) AF: 0.000831 AC: 45 AN: 54124

European-Finnish (FIN) AF: 0.0000494 AC: 2 AN: 40492

Middle Eastern (MID) AF: 0.000968 AC: 4 AN: 4131

European-Non Finnish (NFE) AF: 0.000201 AC: 169 AN: 841463

Other (OTH) AF: 0.00217 AC: 100 AN: 46049

GnomAD4 genome AF: 0.00964 AC: 1084 AN: 112486 Hom.: 10 Cov.: 23 AF XY: 0.00886 AC XY: 307 AN XY: 34648

African (AFR) AF: 0.0332 AC: 1031 AN: 31026

American (AMR) AF: 0.00308 AC: 33 AN: 10709

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.000281 AC: 1 AN: 3558

South Asian (SAS) AF: 0.000735 AC: 2 AN: 2721

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6215

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0000940 AC: 5 AN: 53165

Other (OTH) AF: 0.00780 AC: 12 AN: 1538

Alfa AF: 0.00504 Hom.: 16

Bravo AF: 0.0110

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Spastic paraplegia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.27
DANN	Benign	0.55
PhyloP100		-4.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35151382; hg19: chrX-153135929; COSMIC: COSV100649054; COSMIC: COSV100649054;