X-153866869-C-T

Variant names:

• chrX-153866869-C-T
• rs146782397
• NM_001278116.2:c.2211G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001278116.2(L1CAM):​c.2211G>A​(p.Pro737Pro) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000962 in 1,205,873 control chromosomes in the GnomAD database, including 4 homozygotes. There are 542 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P737P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., 17 hem., cov: 22)
  • Exomes 𝑓: 0.0010 (4 hom. 525 hem.)
• Consequence: L1CAM NM_001278116.2 splice_region, synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.87
• Publications: 1 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.032).
• BP6: Variant X-153866869-C-T is Benign according to our data. Variant chrX-153866869-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 211338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.87 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000564 (63/111775) while in subpopulation SAS AF = 0.00856 (23/2686). AF 95% confidence interval is 0.00585. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 17 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.2211G>A	p.Pro737Pro	splice_region synonymous	Exon 19 of 29	NP_001265045.1	P32004-1
	L1CAM	NM_000425.5		c.2211G>A	p.Pro737Pro	splice_region synonymous	Exon 18 of 28	NP_000416.1	P32004-1
	L1CAM	NM_024003.3		c.2211G>A	p.Pro737Pro	splice_region synonymous	Exon 18 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.2211G>A	p.Pro737Pro	splice_region synonymous	Exon 19 of 29	ENSP00000359077.1	P32004-1
	L1CAM	ENST00000361699.8	TSL:1	c.2211G>A	p.Pro737Pro	splice_region synonymous	Exon 18 of 27	ENSP00000355380.4	P32004-2
	L1CAM	ENST00000361981.7	TSL:1	c.2196G>A	p.Pro732Pro	splice_region synonymous	Exon 17 of 26	ENSP00000354712.3	P32004-3

Frequencies

GnomAD3 genomes AF: 0.000573 AC: 64 AN: 111722 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000979

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000284

Gnomad ASJ AF: 0.00151

Gnomad EAS AF: 0.000281

Gnomad SAS AF: 0.00891

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000490

Gnomad OTH AF: 0.00201

GnomAD2 exomes AF: 0.00171 AC: 306 AN: 179429 AF XY: 0.00256

Gnomad AFR exome AF: 0.000156

Gnomad AMR exome AF: 0.000330

Gnomad ASJ exome AF: 0.00135

Gnomad EAS exome AF: 0.0000727

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000997

Gnomad OTH exome AF: 0.00157

GnomAD4 exome AF: 0.00100 AC: 1097 AN: 1094098 Hom.: 4 Cov.: 31 AF XY: 0.00146 AC XY: 525 AN XY: 359766

African (AFR) AF: 0.000152 AC: 4 AN: 26347

American (AMR) AF: 0.000370 AC: 13 AN: 35143

Ashkenazi Jewish (ASJ) AF: 0.00129 AC: 25 AN: 19354

East Asian (EAS) AF: 0.00 AC: 0 AN: 30176

South Asian (SAS) AF: 0.0106 AC: 571 AN: 54031

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40027

Middle Eastern (MID) AF: 0.0107 AC: 41 AN: 3826

European-Non Finnish (NFE) AF: 0.000435 AC: 365 AN: 839267

Other (OTH) AF: 0.00170 AC: 78 AN: 45927

GnomAD4 genome AF: 0.000564 AC: 63 AN: 111775 Hom.: 0 Cov.: 22 AF XY: 0.000501 AC XY: 17 AN XY: 33965

African (AFR) AF: 0.0000977 AC: 3 AN: 30716

American (AMR) AF: 0.000283 AC: 3 AN: 10590

Ashkenazi Jewish (ASJ) AF: 0.00151 AC: 4 AN: 2645

East Asian (EAS) AF: 0.000281 AC: 1 AN: 3553

South Asian (SAS) AF: 0.00856 AC: 23 AN: 2686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6109

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.000490 AC: 26 AN: 53062

Other (OTH) AF: 0.00198 AC: 3 AN: 1512

Alfa AF: 0.00130 Hom.: 8

Bravo AF: 0.000499

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	-0.72
CADD	Benign	0.27
DANN	Benign	0.81
PhyloP100		-3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

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: rs146782397; hg19: chrX-153132324;