chr1-203216965-G-C

Variant names:

• chr1-203216965-G-C
• rs1065761
• NM_003465.3:c.1325C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003465.3(CHIT1):​c.1325C>G​(p.Ala442Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,614,100 control chromosomes in the GnomAD database, including 12,183 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A442V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.12 (1172 hom., cov: 33)
  • Exomes 𝑓: 0.12 (11011 hom.)
• Consequence: CHIT1 NM_003465.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0810
• Publications: 33 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013396144).
• BP6: Variant 1-203216965-G-C is Benign according to our data. Variant chr1-203216965-G-C is described in ClinVar as Benign. ClinVar VariationId is 294910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003465.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHIT1	NM_003465.3	MANE Select	c.1325C>G	p.Ala442Gly	missense	Exon 11 of 11	NP_003456.1
	CHIT1	NM_001256125.2		c.1268C>G	p.Ala423Gly	missense	Exon 10 of 10	NP_001243054.2
	CHIT1	NR_045784.2		n.1590C>G		non_coding_transcript_exon	Exon 13 of 13

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHIT1	ENST00000367229.6	TSL:1 MANE Select	c.1325C>G	p.Ala442Gly	missense	Exon 11 of 11	ENSP00000356198.1
	CHIT1	ENST00000491855.5	TSL:1	n.*232C>G		non_coding_transcript_exon	Exon 12 of 12	ENSP00000423778.1
	CHIT1	ENST00000503786.1	TSL:1	n.*467C>G		non_coding_transcript_exon	Exon 13 of 13	ENSP00000421617.1

Frequencies

GnomAD3 genomes AF: 0.119 AC: 18101 AN: 152126 Hom.: 1161 Cov.: 33

Gnomad AFR AF: 0.0998

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.0637

Gnomad SAS AF: 0.0972

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.131

GnomAD2 exomes AF: 0.125 AC: 31316 AN: 251060 AF XY: 0.122

Gnomad AFR exome AF: 0.102

Gnomad AMR exome AF: 0.182

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.0704

Gnomad FIN exome AF: 0.168

Gnomad NFE exome AF: 0.119

Gnomad OTH exome AF: 0.118

GnomAD4 exome AF: 0.120 AC: 175693 AN: 1461856 Hom.: 11011 Cov.: 33 AF XY: 0.120 AC XY: 86984 AN XY: 727228

African (AFR) AF: 0.0931 AC: 3116 AN: 33480

American (AMR) AF: 0.181 AC: 8083 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 2815 AN: 26134

East Asian (EAS) AF: 0.0809 AC: 3212 AN: 39700

South Asian (SAS) AF: 0.102 AC: 8799 AN: 86258

European-Finnish (FIN) AF: 0.162 AC: 8634 AN: 53396

Middle Eastern (MID) AF: 0.0725 AC: 418 AN: 5768

European-Non Finnish (NFE) AF: 0.121 AC: 134029 AN: 1112002

Other (OTH) AF: 0.109 AC: 6587 AN: 60396

GnomAD4 genome AF: 0.119 AC: 18150 AN: 152244 Hom.: 1172 Cov.: 33 AF XY: 0.121 AC XY: 9032 AN XY: 74424

African (AFR) AF: 0.100 AC: 4173 AN: 41552

American (AMR) AF: 0.136 AC: 2080 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 354 AN: 3470

East Asian (EAS) AF: 0.0640 AC: 332 AN: 5186

South Asian (SAS) AF: 0.0965 AC: 465 AN: 4820

European-Finnish (FIN) AF: 0.178 AC: 1891 AN: 10600

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.124 AC: 8463 AN: 68002

Other (OTH) AF: 0.133 AC: 281 AN: 2108

Alfa AF: 0.108 Hom.: 686

Bravo AF: 0.119

TwinsUK AF: 0.121 AC: 447

ALSPAC AF: 0.122 AC: 471

ESP6500AA AF: 0.0992 AC: 437

ESP6500EA AF: 0.112 AC: 963

ExAC AF: 0.122 AC: 14852

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Chitotriosidase deficiency Benign:2

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Oct 22, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	2.9
DANN	Benign	0.79
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.0019	N
LIST_S2	Benign	0.031	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.8	N
PhyloP100		0.081
PrimateAI	Benign	0.32	T
PROVEAN	Benign	2.1	N
REVEL	Benign	0.022
Sift	Benign	0.72	T
Sift4G	Benign	0.77	T
Polyphen		0.0	B
Vest4		0.015
MPC		0.093
ClinPred		0.00043	T
GERP RS		3.1
Varity_R		0.15
gMVP		0.27
Mutation Taster		=99/1	polymorphism (auto)

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: rs1065761; hg19: chr1-203186093; COSMIC: COSV55145679; COSMIC: COSV55145679;