X-153866869-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001278116.2(L1CAM):​c.2211G>A​(p.Pro737=) 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 (★★).

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

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -3.87
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.72).
BP6
Variant X-153866869-C-T is Benign according to our data. Variant chrX-153866869-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 211338.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-153866869-C-T is described in Lovd as [Likely_benign]. Variant chrX-153866869-C-T is described in Lovd as [Benign].
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 male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
BS2
High Hemizygotes in GnomAd4 at 17 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
L1CAMNM_001278116.2 linkuse as main transcriptc.2211G>A p.Pro737= splice_region_variant, synonymous_variant 19/29 ENST00000370060.7 NP_001265045.1
L1CAMNM_000425.5 linkuse as main transcriptc.2211G>A p.Pro737= splice_region_variant, synonymous_variant 18/28 NP_000416.1
L1CAMNM_024003.3 linkuse as main transcriptc.2211G>A p.Pro737= splice_region_variant, synonymous_variant 18/27 NP_076493.1
L1CAMNM_001143963.2 linkuse as main transcriptc.2196G>A p.Pro732= splice_region_variant, synonymous_variant 17/26 NP_001137435.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
L1CAMENST00000370060.7 linkuse as main transcriptc.2211G>A p.Pro737= splice_region_variant, synonymous_variant 19/295 NM_001278116.2 ENSP00000359077 A1P32004-1

Frequencies

GnomAD3 genomes
AF:
0.000573
AC:
64
AN:
111722
Hom.:
0
Cov.:
22
AF XY:
0.000501
AC XY:
17
AN XY:
33902
show subpopulations
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
GnomAD3 exomes
AF:
0.00171
AC:
306
AN:
179429
Hom.:
1
AF XY:
0.00256
AC XY:
167
AN XY:
65153
show subpopulations
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 SAS exome
AF:
0.0104
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
show subpopulations
Gnomad4 AFR exome
AF:
0.000152
Gnomad4 AMR exome
AF:
0.000370
Gnomad4 ASJ exome
AF:
0.00129
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0106
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000435
Gnomad4 OTH exome
AF:
0.00170
GnomAD4 genome
AF:
0.000564
AC:
63
AN:
111775
Hom.:
0
Cov.:
22
AF XY:
0.000501
AC XY:
17
AN XY:
33965
show subpopulations
Gnomad4 AFR
AF:
0.0000977
Gnomad4 AMR
AF:
0.000283
Gnomad4 ASJ
AF:
0.00151
Gnomad4 EAS
AF:
0.000281
Gnomad4 SAS
AF:
0.00856
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000490
Gnomad4 OTH
AF:
0.00198
Alfa
AF:
0.00130
Hom.:
8
Bravo
AF:
0.000499

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Likely benign, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoMay 04, 2015- -
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Mar 01, 2016- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxSep 10, 2018- -
Likely benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Spastic paraplegia Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 25, 2024- -
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsMay 28, 2017This 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. -
Hereditary spastic paraplegia Benign:1
Likely benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenDec 12, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.72
CADD
Benign
0.27
DANN
Benign
0.81
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs146782397; hg19: chrX-153132324; API