3-325956-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_006614.4(CHL1):c.92-3T>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,595,674 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (19 hom.)
• Consequence: CHL1 NM_006614.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.06705
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.12

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 3-325956-T-A is Benign according to our data. Variant chr3-325956-T-A is described in ClinVar as [Benign]. Clinvar id is 773668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHL1	NM_006614.4	c.92-3T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000256509.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHL1	ENST00000256509.7	c.92-3T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006614.4	P3

Frequencies

GnomAD3 genomes AF: 0.00179 AC: 272 AN: 152066 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00599

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.0179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00237 AC: 582 AN: 245998 Hom.: 6 AF XY: 0.00230 AC XY: 306 AN XY: 133156

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000202

Gnomad EAS exome AF: 0.00441

Gnomad SAS exome AF: 0.000269

Gnomad FIN exome AF: 0.0178

Gnomad NFE exome AF: 0.000857

Gnomad OTH exome AF: 0.00253

GnomAD4 exome AF: 0.00119 AC: 1712 AN: 1443490 Hom.: 19 Cov.: 27 AF XY: 0.00117 AC XY: 839 AN XY: 718920

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000464

Gnomad4 EAS exome AF: 0.00691

Gnomad4 SAS exome AF: 0.000341

Gnomad4 FIN exome AF: 0.0165

Gnomad4 NFE exome AF: 0.000385

Gnomad4 OTH exome AF: 0.00164

GnomAD4 genome AF: 0.00179 AC: 272 AN: 152184 Hom.: 1 Cov.: 32 AF XY: 0.00271 AC XY: 202 AN XY: 74408

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00600

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.0179

Gnomad4 NFE AF: 0.000662

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000833 Hom.: 0

Bravo AF: 0.000491

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.000111

EpiControl AF: 0.000120

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CHL1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 10, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Mar 29, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
Cadd	Benign	15
Dann	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.067
dbscSNV1_RF	Benign	0.39
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: 11

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

Publications

LitVar

Other links and lift over

dbSNP: rs200543338; hg19: chr3-367639;