rs73640833

chrX-153869924-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.1002C>T(p.Tyr334=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000777 in 1,208,329 control chromosomes in the GnomAD database, including 7 homozygotes. There are 267 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (2 hom., 137 hem., cov: 24)
  • Exomes 𝑓: 0.00043 (5 hom. 130 hem.)
• Consequence: L1CAM NM_001278116.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.00

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=-0.53).
• BP6: Variant X-153869924-G-A is Benign according to our data. Variant chrX-153869924-G-A is described in ClinVar as [Benign]. Clinvar id is 199019.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00412 (463/112355) while in subpopulation AFR AF= 0.0145 (449/30978). AF 95% confidence interval is 0.0134. There are 2 homozygotes in gnomad4. There are 137 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
L1CAM	NM_001278116.2	c.1002C>T	p.Tyr334=	synonymous_variant	10/29	ENST00000370060.7
L1CAM	NM_000425.5	c.1002C>T	p.Tyr334=	synonymous_variant	9/28
L1CAM	NM_024003.3	c.1002C>T	p.Tyr334=	synonymous_variant	9/27
L1CAM	NM_001143963.2	c.987C>T	p.Tyr329=	synonymous_variant	8/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L1CAM	ENST00000370060.7	c.1002C>T	p.Tyr334=	synonymous_variant	10/29	5	NM_001278116.2	A1
L1CAM	ENST00000361699.8	c.1002C>T	p.Tyr334=	synonymous_variant	9/27	1		P4
L1CAM	ENST00000361981.7	c.987C>T	p.Tyr329=	synonymous_variant	8/26	1		A1
L1CAM	ENST00000370055.5	c.987C>T	p.Tyr329=	synonymous_variant	9/27	5		A1

Frequencies

GnomAD3 genomes AF: 0.00413 AC: 464 AN: 112301 Hom.: 2 Cov.: 24 AF XY: 0.00398 AC XY: 137 AN XY: 34457

Gnomad AFR AF: 0.0146

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000933

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00264

GnomAD3 exomes AF: 0.00113 AC: 198 AN: 174874 Hom.: 0 AF XY: 0.00101 AC XY: 63 AN XY: 62596

Gnomad AFR exome AF: 0.0153

Gnomad AMR exome AF: 0.000333

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000131

Gnomad OTH exome AF: 0.000229

GnomAD4 exome AF: 0.000434 AC: 476 AN: 1095974 Hom.: 5 Cov.: 34 AF XY: 0.000359 AC XY: 130 AN XY: 361830

Gnomad4 AFR exome AF: 0.0151

Gnomad4 AMR exome AF: 0.000628

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000556

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000166

Gnomad4 OTH exome AF: 0.000805

GnomAD4 genome AF: 0.00412 AC: 463 AN: 112355 Hom.: 2 Cov.: 24 AF XY: 0.00397 AC XY: 137 AN XY: 34521

Gnomad4 AFR AF: 0.0145

Gnomad4 AMR AF: 0.000932

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00261

Alfa AF: 0.00230 Hom.: 14

Bravo AF: 0.00467

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 12, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 07, 2016	- -

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

Apr 13, 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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 05, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	4.3
Dann	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs73640833; hg19: chrX-153135379;