dbSNP rs880633: CHI3L1:p.Arg145Gly (chr1-203183673-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001276.4(CHI3L1):c.433A>G(p.Arg145Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.49 in 1,613,670 control chromosomes in the GnomAD database, including 199,632 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

Frequency

Genomes: 𝑓 0.41 ( 14516 hom., cov: 32)

Exomes 𝑓: 0.50 ( 185116 hom. )

Consequence

CHI3L1
NM_001276.4 missense

Scores

Clinical Significance

drug response no assertion criteria provided O:1

Conservation

PhyloP100: 2.10

Publications

80 publications found

Variant links:

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)

CHI3L1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004434228).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.522 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHI3L1	NM_001276.4 link	c.433A>G	p.Arg145Gly	missense_variant	Exon 5 of 10	ENST00000255409.8	NP_001267.2	P36222A0A024R969

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHI3L1	ENST00000255409.8 link	c.433A>G	p.Arg145Gly	missense_variant	Exon 5 of 10	1	NM_001276.4	ENSP00000255409.3		P36222

Frequencies

GnomAD3 genomes

AF:

0.415

AC:

63070

AN:

151910

Hom.:

14515

Cov.:

show subpopulations

Gnomad AFR

AF:

0.216

Gnomad AMI

AF:

0.612

Gnomad AMR

AF:

0.344

Gnomad ASJ

AF:

0.422

Gnomad EAS

AF:

0.372

Gnomad SAS

AF:

0.478

Gnomad FIN

AF:

0.553

Gnomad MID

AF:

0.434

Gnomad NFE

AF:

0.526

Gnomad OTH

AF:

0.419

GnomAD2 exomes

AF:

0.450

AC:

113050

AN:

251364

AF XY:

0.463

show subpopulations

Gnomad AFR exome

AF:

0.214

Gnomad AMR exome

AF:

0.263

Gnomad ASJ exome

AF:

0.434

Gnomad EAS exome

AF:

0.375

Gnomad FIN exome

AF:

0.545

Gnomad NFE exome

AF:

0.531

Gnomad OTH exome

AF:

0.445

GnomAD4 exome

AF:

0.498

AC:

727640

AN:

1461642

Hom.:

185116

Cov.:

AF XY:

0.499

AC XY:

362705

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.202

AC:

6752

AN:

33478

American (AMR)

AF:

0.274

AC:

12234

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.438

AC:

11454

AN:

26134

East Asian (EAS)

AF:

0.368

AC:

14590

AN:

39698

South Asian (SAS)

AF:

0.469

AC:

40438

AN:

86254

European-Finnish (FIN)

AF:

0.544

AC:

29070

AN:

53400

Middle Eastern (MID)

AF:

0.439

AC:

2529

AN:

5756

European-Non Finnish (NFE)

AF:

0.524

AC:

582432

AN:

1111812

Other (OTH)

AF:

0.466

AC:

28141

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

19272

38543

57815

77086

96358

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16432

32864

49296

65728

82160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.415

AC:

63088

AN:

152028

Hom.:

14516

Cov.:

AF XY:

0.416

AC XY:

30914

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.216

AC:

8961

AN:

41460

American (AMR)

AF:

0.344

AC:

5258

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.422

AC:

1463

AN:

3470

East Asian (EAS)

AF:

0.372

AC:

1928

AN:

5176

South Asian (SAS)

AF:

0.478

AC:

2299

AN:

4806

European-Finnish (FIN)

AF:

0.553

AC:

5845

AN:

10566

Middle Eastern (MID)

AF:

0.435

AC:

128

AN:

294

European-Non Finnish (NFE)

AF:

0.526

AC:

35763

AN:

67946

Other (OTH)

AF:

0.419

AC:

885

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1787

3574

5361

7148

8935

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

596

1192

1788

2384

2980

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.489

Hom.:

89339

Bravo

AF:

0.386

TwinsUK

AF:

0.524

AC:

1943

ALSPAC

AF:

0.519

AC:

2000

ESP6500AA

AF:

0.220

AC:

968

ESP6500EA

AF:

0.514

AC:

4422

ExAC

AF:

0.455

AC:

55239

Asia WGS

AF:

0.396

AC:

1381

AN:

3478

EpiCase

AF:

0.519

EpiControl

AF:

0.526

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Thalidomide response

Other:1

Rare Diseases Genetics and Genomics, Islamia College Peshawar

Significance:drug response

Review Status:no assertion criteria provided

Collection Method:research

this variant was associated with excellent response to thalidomide (achieving transfusion independence) excellent responsive

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

Eigen

Benign

0.18

Eigen_PC

Benign

0.17

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.75

MetaRNN

Benign

0.0044

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.7

PhyloP100

2.1

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-3.3

REVEL

Benign

0.098

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0010

Polyphen

0.85

Vest4

0.085

MPC

0.23

ClinPred

0.020

GERP RS

5.7

Varity_R

0.60

gMVP

0.35

Mutation Taster

=77/23

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over