X-153868916-G-T

Variant names:

• chrX-153868916-G-T
• NM_001278116.2:c.1304C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001278116.2(L1CAM):​c.1304C>A​(p.Thr435Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,275 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: L1CAM NM_001278116.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.432

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a domain Ig-like C2-type 5 (size 82) in uniprot entity L1CAM_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_001278116.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29341137).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L1CAM	NM_001278116.2	c.1304C>A	p.Thr435Lys	missense_variant	Exon 12 of 29	ENST00000370060.7	NP_001265045.1
L1CAM	NM_000425.5	c.1304C>A	p.Thr435Lys	missense_variant	Exon 11 of 28		NP_000416.1
L1CAM	NM_024003.3	c.1304C>A	p.Thr435Lys	missense_variant	Exon 11 of 27		NP_076493.1
L1CAM	NM_001143963.2	c.1289C>A	p.Thr430Lys	missense_variant	Exon 10 of 26		NP_001137435.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L1CAM	ENST00000370060.7	c.1304C>A	p.Thr435Lys	missense_variant	Exon 12 of 29	5	NM_001278116.2	ENSP00000359077.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097275 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 362665

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	13
DANN	Benign	0.92
DEOGEN2	Benign	0.37	.;T;.;.
FATHMM_MKL	Benign	0.28	N
LIST_S2	Uncertain	0.88	D;D;.;D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.29	T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.62	.;N;.;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.72	N;N;N;N
REVEL	Uncertain	0.43
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	0.93	T;T;T;T
Polyphen		0.84, 0.47	.;P;.;P
Vest4		0.39
MutPred		0.58		.;Gain of ubiquitination at T435 (P = 0.0219);.;Gain of ubiquitination at T435 (P = 0.0219);
MVP		0.96
MPC		1.6
ClinPred		0.32	T
GERP RS		5.5
Varity_R		0.28
gMVP		0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-153134371;