3-328295-G-T

Position:

• chr3-328295-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_006614.4(CHL1):​c.326G>T​(p.Cys109Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHL1 NM_006614.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.35

Genes affected

CHL1 (HGNC:1939): (cell adhesion molecule L1 like) The protein encoded by this gene is a member of the L1 gene family of neural cell adhesion molecules. It is a neural recognition molecule that may be involved in signal transduction pathways. The deletion of one copy of this gene may be responsible for mental defects in patients with 3p- syndrome. This protein may also play a role in the growth of certain cancers. Alternate splicing results in both coding and non-coding variants. [provided by RefSeq, Nov 2011]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.977

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHL1	NM_006614.4	c.326G>T	p.Cys109Phe	missense_variant	5/28	ENST00000256509.7	NP_006605.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHL1	ENST00000256509.7	c.326G>T	p.Cys109Phe	missense_variant	5/28	1	NM_006614.4	ENSP00000256509.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 09, 2024

The c.326G>T (p.C109F) alteration is located in exon 5 (coding exon 3) of the CHL1 gene. This alteration results from a G to T substitution at nucleotide position 326, causing the cysteine (C) at amino acid position 109 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	.;D;.;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	1.0	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Pathogenic	-9.9	D;D;D;.
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;.;.
Vest4		0.95
MutPred		0.84		Loss of catalytic residue at C109 (P = 0.0762);Loss of catalytic residue at C109 (P = 0.0762);Loss of catalytic residue at C109 (P = 0.0762);Loss of catalytic residue at C109 (P = 0.0762);
MVP		0.93
MPC		0.078
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.96
gMVP		0.94

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: chr3-369978;