rs144605615

chrX-153875809-G-AchrX-153875809-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001278116.2(L1CAM):c.28C>T(p.Pro10Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,208,295 control chromosomes in the GnomAD database, including 18 homozygotes. There are 492 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (10 hom., 238 hem., cov: 23)
  • Exomes 𝑓: 0.00089 (8 hom. 254 hem.)
• Consequence: L1CAM NM_001278116.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.56

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008834422).
• BP6: Variant X-153875809-G-A is Benign according to our data. Variant chrX-153875809-G-A is described in ClinVar as [Benign]. Clinvar id is 92930.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00892 (995/111555) while in subpopulation AFR AF= 0.0312 (955/30653). AF 95% confidence interval is 0.0295. There are 10 homozygotes in gnomad4. There are 238 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
L1CAM	NM_001278116.2	c.28C>T	p.Pro10Ser	missense_variant	2/29	ENST00000370060.7
L1CAM	NM_000425.5	c.28C>T	p.Pro10Ser	missense_variant	1/28
L1CAM	NM_024003.3	c.28C>T	p.Pro10Ser	missense_variant	1/27
L1CAM	NM_001143963.2	c.28C>T	p.Pro10Ser	missense_variant	1/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L1CAM	ENST00000370060.7	c.28C>T	p.Pro10Ser	missense_variant	2/29	5	NM_001278116.2	A1

Frequencies

GnomAD3 genomes AF: 0.00891 AC: 993 AN: 111504 Hom.: 10 Cov.: 23 AF XY: 0.00703 AC XY: 237 AN XY: 33716

Gnomad AFR AF: 0.0312

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00244

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0125

Gnomad NFE AF: 0.0000378

Gnomad OTH AF: 0.00597

GnomAD3 exomes AF: 0.00261 AC: 473 AN: 180985 Hom.: 5 AF XY: 0.00151 AC XY: 100 AN XY: 66223

Gnomad AFR exome AF: 0.0337

Gnomad AMR exome AF: 0.000987

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: 0.0000123

Gnomad OTH exome AF: 0.00111

GnomAD4 exome AF: 0.000894 AC: 980 AN: 1096740 Hom.: 8 Cov.: 31 AF XY: 0.000701 AC XY: 254 AN XY: 362462

Gnomad4 AFR exome AF: 0.0323

Gnomad4 AMR exome AF: 0.00111

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000131

Gnomad4 OTH exome AF: 0.00156

GnomAD4 genome AF: 0.00892 AC: 995 AN: 111555 Hom.: 10 Cov.: 23 AF XY: 0.00705 AC XY: 238 AN XY: 33777

Gnomad4 AFR AF: 0.0312

Gnomad4 AMR AF: 0.00244

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000378

Gnomad4 OTH AF: 0.00589

Alfa AF: 0.00125 Hom.: 56

Bravo AF: 0.0104

ESP6500AA AF: 0.0321 AC: 123

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00282 AC: 342

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 30, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 01, 2013	- -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 24, 2015

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	19
Dann	Uncertain	0.99
FATHMM_MKL	Benign	0.015	N
LIST_S2	Uncertain	0.90	D;D;.;D;D;D;D;D
MetaRNN	Benign	0.0088	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;N;N;N;.;.;.;.
MutationTaster	Benign	0.95	N;N;N;N;N;N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.42	N;N;N;N;N;N;N;N
REVEL	Benign	0.096
Sift	Uncertain	0.010	D;D;D;D;T;T;T;D
Sift4G	Benign	0.53	T;T;T;T;.;.;D;.
Polyphen		0.046, 0.0090	.;B;.;B;.;.;.;.
Vest4		0.27
MVP		0.63
MPC		0.55
ClinPred		0.018	T
GERP RS		2.7
Varity_R		0.081
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs144605615; hg19: chrX-153141264; COSMIC: COSV99051951; COSMIC: COSV99051951;