X-153864014-C-T

Variant names:

• chrX-153864014-C-T
• rs782420127
• NM_001278116.2:c.3326G>A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001278116.2(L1CAM):​c.3326G>A​(p.Arg1109His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000182 in 1,097,584 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 25)
  • Exomes 𝑓: 0.000018 (0 hom. 9 hem.)
• Consequence: L1CAM NM_001278116.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.228

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.056392938).
• BP6: Variant X-153864014-C-T is Benign according to our data. Variant chrX-153864014-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 586124.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000182 (20/1097584) while in subpopulation SAS AF= 0.000222 (12/54053). AF 95% confidence interval is 0.000128. There are 0 homozygotes in gnomad4_exome. There are 9 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAdExome4 at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L1CAM	NM_001278116.2	c.3326G>A	p.Arg1109His	missense_variant	Exon 26 of 29	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.3326G>A	p.Arg1109His	missense_variant	Exon 25 of 28		NP_000416.1
L1CAM	NM_024003.3	c.3326G>A	p.Arg1109His	missense_variant	Exon 25 of 27		NP_076493.1
L1CAM	NM_001143963.2	c.3311G>A	p.Arg1104His	missense_variant	Exon 24 of 26		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7	c.3326G>A	p.Arg1109His	missense_variant	Exon 26 of 29	5	NM_001278116.2	ENSP00000359077.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD3 exomes AF: 0.0000222 AC: 4 AN: 180341 Hom.: 0 AF XY: 0.0000457 AC XY: 3 AN XY: 65589

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000366

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000725

Gnomad SAS exome AF: 0.000106

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000182 AC: 20 AN: 1097584 Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 9 AN XY: 363006

Gnomad4 AFR exome AF: 0.0000758

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000133

Gnomad4 SAS exome AF: 0.000222

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 25

Bravo AF: 0.00000378

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

May 09, 2018

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Spastic paraplegia Benign:1

Jul 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.8
DANN	Benign	0.81
DEOGEN2	Benign	0.34	.;T;.;.
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.85	D;D;.;D
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.056	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	.;N;.;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.33	N;N;N;N
REVEL	Benign	0.020
Sift	Benign	0.53	T;T;T;T
Sift4G	Benign	0.56	T;T;T;T
Polyphen		0.0010, 0.0060	.;B;.;B
Vest4		0.034
MutPred		0.41		.;Loss of methylation at R1109 (P = 0.0188);.;Loss of methylation at R1109 (P = 0.0188);
MVP		0.28
MPC		0.67
ClinPred		0.026	T
GERP RS		1.0
Varity_R		0.029
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs782420127; hg19: chrX-153129469; COSMIC: COSV62826698; COSMIC: COSV62826698;