chr1-203179515-C-A

Variant names:

• chr1-203179515-C-A
• rs370960745
• NM_001276.4:c.1082G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001276.4(CHI3L1):​c.1082G>T​(p.Gly361Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000695 in 1,437,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. G361D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CHI3L1 NM_001276.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.53
• Publications: 0 publications found

Genes affected

CHI3L1 (HGNC:1932): (chitinase 3 like 1) Chitinases catalyze the hydrolysis of chitin, which is an abundant glycopolymer found in insect exoskeletons and fungal cell walls. The glycoside hydrolase 18 family of chitinases includes eight human family members. This gene encodes a glycoprotein member of the glycosyl hydrolase 18 family. The protein lacks chitinase activity and is secreted by activated macrophages, chondrocytes, neutrophils and synovial cells. The protein is thought to play a role in the process of inflammation and tissue remodeling. [provided by RefSeq, Sep 2009]

CHI3L1 Gene-Disease associations (from GenCC):

• schizophrenia

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001276.4. 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
	CHI3L1	NM_001276.4	MANE Select	c.1082G>T	p.Gly361Val	missense	Exon 10 of 10	NP_001267.2	P36222

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHI3L1	ENST00000255409.8	TSL:1 MANE Select	c.1082G>T	p.Gly361Val	missense	Exon 10 of 10	ENSP00000255409.3	P36222
	CHI3L1	ENST00000874779.1		c.1292G>T	p.Gly431Val	missense	Exon 12 of 12	ENSP00000544838.1
	CHI3L1	ENST00000874774.1		c.1100G>T	p.Gly367Val	missense	Exon 10 of 10	ENSP00000544833.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1437956 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 712338

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32588

American (AMR) AF: 0.00 AC: 0 AN: 41630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24670

East Asian (EAS) AF: 0.00 AC: 0 AN: 39302

South Asian (SAS) AF: 0.00 AC: 0 AN: 83930

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52840

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5630

European-Non Finnish (NFE) AF: 9.11e-7 AC: 1 AN: 1098240

Other (OTH) AF: 0.00 AC: 0 AN: 59126

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Benign	-0.0076	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.51	T
MutationAssessor	Pathogenic	4.6	H
PhyloP100		4.5
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-8.6	D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.55
MutPred		0.87		Loss of catalytic residue at G361 (P = 0.2986)
MVP		0.52
MPC		0.46
ClinPred		0.98	D
GERP RS		2.8
Varity_R		0.86
gMVP		0.61
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: -17

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

Other links and lift over

dbSNP: rs370960745; hg19: chr1-203148643;