rs200638763

chrX-153870063-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001278116.2(L1CAM):c.984C>T(p.Thr328=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000196 in 1,210,304 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 79 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 0.00029 (0 hom., 14 hem., cov: 24)
  • Exomes 𝑓: 0.00019 (0 hom. 65 hem.)
• Consequence: L1CAM NM_001278116.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.93

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant X-153870063-G-A is Benign according to our data. Variant chrX-153870063-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 458216.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153870063-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.93 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000293 (33/112521) while in subpopulation AMR AF= 0.0013 (14/10733). AF 95% confidence interval is 0.000788. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 14 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
L1CAM	NM_001278116.2	c.984C>T	p.Thr328=	synonymous_variant	9/29	ENST00000370060.7
L1CAM	NM_000425.5	c.984C>T	p.Thr328=	synonymous_variant	8/28
L1CAM	NM_024003.3	c.984C>T	p.Thr328=	synonymous_variant	8/27
L1CAM	NM_001143963.2	c.969C>T	p.Thr323=	synonymous_variant	7/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L1CAM	ENST00000370060.7	c.984C>T	p.Thr328=	synonymous_variant	9/29	5	NM_001278116.2	A1
L1CAM	ENST00000361699.8	c.984C>T	p.Thr328=	synonymous_variant	8/27	1		P4
L1CAM	ENST00000361981.7	c.969C>T	p.Thr323=	synonymous_variant	7/26	1		A1
L1CAM	ENST00000370055.5	c.969C>T	p.Thr323=	synonymous_variant	8/27	5		A1

Frequencies

GnomAD3 genomes AF: 0.000293 AC: 33 AN: 112468 Hom.: 0 Cov.: 24 AF XY: 0.000404 AC XY: 14 AN XY: 34626

Gnomad AFR AF: 0.0000968

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.000244

Gnomad OTH AF: 0.00132

GnomAD3 exomes AF: 0.000372 AC: 68 AN: 182756 Hom.: 0 AF XY: 0.000252 AC XY: 17 AN XY: 67384

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.00146

Gnomad ASJ exome AF: 0.000401

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000251

Gnomad NFE exome AF: 0.000246

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000186 AC: 204 AN: 1097783 Hom.: 0 Cov.: 33 AF XY: 0.000179 AC XY: 65 AN XY: 363251

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.00122

Gnomad4 ASJ exome AF: 0.000310

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000298

Gnomad4 NFE exome AF: 0.000134

Gnomad4 OTH exome AF: 0.000412

GnomAD4 genome AF: 0.000293 AC: 33 AN: 112521 Hom.: 0 Cov.: 24 AF XY: 0.000404 AC XY: 14 AN XY: 34689

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.00130

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000244

Gnomad4 OTH AF: 0.00130

Alfa AF: 0.000400 Hom.: 3

Bravo AF: 0.000310

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 26, 2018

- -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 28, 2017

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.055
Dann	Benign	0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs200638763; hg19: chrX-153135518;