3-377863-A-T

Variant names:

• chr3-377863-A-T
• rs149981944
• NM_006614.4:c.1797A>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_006614.4(CHL1):​c.1797A>T​(p.Leu599Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000289 in 1,611,394 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (3 hom.)
• Consequence: CHL1 NM_006614.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.157
• Publications: 1 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-AS1 (HGNC:40148): (CHL1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005228877).
• BP6: Variant 3-377863-A-T is Benign according to our data. Variant chr3-377863-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 710904.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 232 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.1797A>T	p.Leu599Phe	missense	Exon 16 of 28	NP_006605.2
	CHL1	NM_001253387.2		c.1749A>T	p.Leu583Phe	missense	Exon 15 of 27	NP_001240316.1	O00533-1
	CHL1	NM_001253388.1		c.1797A>T	p.Leu599Phe	missense	Exon 14 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.1797A>T	p.Leu599Phe	missense	Exon 16 of 28	ENSP00000256509.2	O00533-2
	CHL1	ENST00000397491.6	TSL:1	c.1749A>T	p.Leu583Phe	missense	Exon 15 of 27	ENSP00000380628.2	O00533-1
	CHL1	ENST00000620033.4	TSL:1	c.1797A>T	p.Leu599Phe	missense	Exon 14 of 25	ENSP00000483512.1	A0A087X0M8

Frequencies

GnomAD3 genomes AF: 0.00152 AC: 232 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00552

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000383 AC: 96 AN: 250904 AF XY: 0.000251

Gnomad AFR exome AF: 0.00554

Gnomad AMR exome AF: 0.0000872

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000160 AC: 233 AN: 1459076 Hom.: 3 Cov.: 29 AF XY: 0.000128 AC XY: 93 AN XY: 726000

African (AFR) AF: 0.00563 AC: 188 AN: 33388

American (AMR) AF: 0.000224 AC: 10 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1109714

Other (OTH) AF: 0.000249 AC: 15 AN: 60280

GnomAD4 genome AF: 0.00152 AC: 232 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.00158 AC XY: 118 AN XY: 74474

African (AFR) AF: 0.00551 AC: 229 AN: 41574

American (AMR) AF: 0.000131 AC: 2 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.0000908 Hom.: 0

Bravo AF: 0.00164

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000494 AC: 60

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	CHL1-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	3.1
DANN	Benign	0.85
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.055	N
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.0031	T
MetaRNN	Benign	0.0052	T
MetaSVM	Benign	-0.98	T
PhyloP100		-0.16
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.083
Sift	Benign	0.11	T
Sift4G	Benign	0.71	T
Polyphen		0.023	B
Vest4		0.052
MutPred		0.46		Loss of glycosylation at S579 (P = 0.084)
MVP		0.088
MPC		0.012
ClinPred		0.027	T
GERP RS		-1.3
Varity_R		0.065
gMVP		0.21
Mutation Taster		=99/1	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: rs149981944; hg19: chr3-419546;