NM_003465.3:c.1060G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBA1

The NM_003465.3(CHIT1):c.1060G>A(p.Gly354Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00451 in 1,613,924 control chromosomes in the GnomAD database, including 268 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 133 hom., cov: 33)

Exomes 𝑓: 0.0025 ( 135 hom. )

Consequence

CHIT1
NM_003465.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:3

Conservation

PhyloP100: 7.10

Publications

18 publications found

Variant links:

Genes affected

CHIT1 (HGNC:1936): (chitinase 1) Chitotriosidase is secreted by activated human macrophages and is markedly elevated in plasma of Gaucher disease patients. The expression of chitotriosidase occurs only at a late stage of differentiation of monocytes to activated macrophages in culture. Human macrophages can synthesize a functional chitotriosidase, a highly conserved enzyme with a strongly regulated expression. This enzyme may play a role in the degradation of chitin-containing pathogens. Several alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Jan 2012]

CHIT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.008951932).

BP6

Variant 1-203217835-C-T is Benign according to our data. Variant chr1-203217835-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 472285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0796 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHIT1	NM_003465.3 link	c.1060G>A	p.Gly354Arg	missense_variant	Exon 10 of 11	ENST00000367229.6	NP_003456.1	Q13231-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHIT1	ENST00000367229.6 link	c.1060G>A	p.Gly354Arg	missense_variant	Exon 10 of 11	1	NM_003465.3	ENSP00000356198.1		Q13231-1

Frequencies

GnomAD3 genomes

AF:

0.0236

AC:

3591

AN:

152206

Hom.:

132

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0817

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00903

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000426

Gnomad OTH

AF:

0.0172

GnomAD2 exomes

AF:

0.00619

AC:

1547

AN:

250120

AF XY:

0.00437

show subpopulations

Gnomad AFR exome

AF:

0.0832

Gnomad AMR exome

AF:

0.00424

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000212

Gnomad OTH exome

AF:

0.00295

GnomAD4 exome

AF:

0.00251

AC:

3663

AN:

1461600

Hom.:

135

Cov.:

AF XY:

0.00224

AC XY:

1630

AN XY:

727084

show subpopulations

African (AFR)

AF:

0.0854

AC:

2858

AN:

33474

American (AMR)

AF:

0.00483

AC:

216

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.000476

AC:

AN:

86216

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00785

AC:

AN:

5736

European-Non Finnish (NFE)

AF:

0.000143

AC:

159

AN:

1111918

Other (OTH)

AF:

0.00568

AC:

343

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

199

398

598

797

996

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

264

352

440

<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:

0.0237

AC:

3611

AN:

152324

Hom.:

133

Cov.:

AF XY:

0.0222

AC XY:

1657

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.0819

AC:

3404

AN:

41556

American (AMR)

AF:

0.00901

AC:

138

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000426

AC:

AN:

68038

Other (OTH)

AF:

0.0175

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

169

338

506

675

844

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<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:

0.00846

Hom.:

173

Bravo

AF:

0.0273

ESP6500AA

AF:

0.0783

AC:

345

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00763

AC:

926

EpiCase

AF:

0.000109

EpiControl

AF:

0.000416

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 16, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Chitotriosidase deficiency

Benign:2

Nov 18, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Uncertain

0.096

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.50

D;.

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

D;D

MetaRNN

Benign

0.0090

T;T

MetaSVM

Benign

-0.34

MutationAssessor

Pathogenic

4.8

H;.

PhyloP100

7.1

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-7.1

D;D

REVEL

Pathogenic

0.87

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.96

MutPred

0.91

Gain of MoRF binding (P = 0.0162);.;

MVP

0.97

MPC

0.54

ClinPred

0.11

GERP RS

3.8

Varity_R

0.98

gMVP

0.96

Mutation Taster

=45/55

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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