chr3-328292-G-A

Variant names:

• chr3-328292-G-A
• rs369767790
• NM_006614.4:c.323G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The NM_006614.4(CHL1):​c.323G>A​(p.Arg108His) variant causes a missense change. The variant allele was found at a frequency of 0.0000434 in 1,612,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R108L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: CHL1 NM_006614.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.43
• 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=0.38861263).
• BP6: Variant 3-328292-G-A is Benign according to our data. Variant chr3-328292-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1108288.
• BS2: High AC in GnomAd4 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.323G>A	p.Arg108His	missense	Exon 5 of 28	NP_006605.2
	CHL1	NM_001253387.2		c.323G>A	p.Arg108His	missense	Exon 5 of 27	NP_001240316.1	O00533-1
	CHL1	NM_001253388.1		c.323G>A	p.Arg108His	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.323G>A	p.Arg108His	missense	Exon 5 of 28	ENSP00000256509.2	O00533-2
	CHL1	ENST00000397491.6	TSL:1	c.323G>A	p.Arg108His	missense	Exon 5 of 27	ENSP00000380628.2	O00533-1
	CHL1	ENST00000620033.4	TSL:1	c.323G>A	p.Arg108His	missense	Exon 3 of 25	ENSP00000483512.1	A0A087X0M8

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152046 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000679 AC: 17 AN: 250338 AF XY: 0.0000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000293

Gnomad ASJ exome AF: 0.000795

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000432 AC: 63 AN: 1459986 Hom.: 0 Cov.: 30 AF XY: 0.0000496 AC XY: 36 AN XY: 726298

African (AFR) AF: 0.00 AC: 0 AN: 33382

American (AMR) AF: 0.0000224 AC: 1 AN: 44586

Ashkenazi Jewish (ASJ) AF: 0.000729 AC: 19 AN: 26056

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86090

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5756

European-Non Finnish (NFE) AF: 0.00000900 AC: 10 AN: 1110832

Other (OTH) AF: 0.000149 AC: 9 AN: 60304

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152046 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74270

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67972

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000101 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000741 AC: 9

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.33	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.39	T
MetaSVM	Uncertain	0.12	D
PhyloP100		5.4
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.39
MVP		0.81
MPC		0.016
ClinPred		0.62	D
GERP RS		5.0
Varity_R		0.47
gMVP		0.68
Mutation Taster		=59/41	polymorphism

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

Other links and lift over

dbSNP: rs369767790; hg19: chr3-369975; COSMIC: COSV56586782; COSMIC: COSV56586782;