3-328192-C-T

Variant names:

• chr3-328192-C-T
• rs954598804
• NM_006614.4:c.223C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_006614.4(CHL1):​c.223C>T​(p.Pro75Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000499 in 1,604,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P75T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CHL1 NM_006614.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.44
• Publications: 2 publications found

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]

CHL1 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• partial deletion of the short arm of chromosome 3

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21834877).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006614.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHL1	NM_006614.4	MANE Select	c.223C>T	p.Pro75Ser	missense	Exon 5 of 28	NP_006605.2
	CHL1	NM_001253387.2		c.223C>T	p.Pro75Ser	missense	Exon 5 of 27	NP_001240316.1	O00533-1
	CHL1	NM_001253388.1		c.223C>T	p.Pro75Ser	missense	Exon 3 of 25	NP_001240317.1	A0A087X0M8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHL1	ENST00000256509.7	TSL:1 MANE Select	c.223C>T	p.Pro75Ser	missense	Exon 5 of 28	ENSP00000256509.2	O00533-2
	CHL1	ENST00000397491.6	TSL:1	c.223C>T	p.Pro75Ser	missense	Exon 5 of 27	ENSP00000380628.2	O00533-1
	CHL1	ENST00000620033.4	TSL:1	c.223C>T	p.Pro75Ser	missense	Exon 3 of 25	ENSP00000483512.1	A0A087X0M8

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151966 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000482 AC: 7 AN: 1452098 Hom.: 0 Cov.: 30 AF XY: 0.00000692 AC XY: 5 AN XY: 722298

African (AFR) AF: 0.00 AC: 0 AN: 33022

American (AMR) AF: 0.00 AC: 0 AN: 43796

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25778

East Asian (EAS) AF: 0.00 AC: 0 AN: 39396

South Asian (SAS) AF: 0.00 AC: 0 AN: 84458

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53168

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00000632 AC: 7 AN: 1106786

Other (OTH) AF: 0.00 AC: 0 AN: 59960

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151966 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74234

African (AFR) AF: 0.00 AC: 0 AN: 41384

American (AMR) AF: 0.00 AC: 0 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67970

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.043	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.22	T
MetaSVM	Uncertain	0.62	D
PhyloP100		1.4
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.41	N
REVEL	Benign	0.13
Sift	Benign	0.092	T
Sift4G	Benign	0.49	T
Polyphen		0.13	B
Vest4		0.17
MutPred		0.47		Gain of glycosylation at T70 (P = 0.0364)
MVP		0.62
MPC		0.021
ClinPred		0.20	T
GERP RS		3.0
Varity_R		0.039
gMVP		0.49
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs954598804; hg19: chr3-369875;