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

Sel.	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	Q13231-1
	CHIT1	NM_001256125.2		c.1268C>G	p.Ala423Gly	missense	Exon 10 of 10	NP_001243054.2	Q13231-4
	CHIT1	NR_045784.2		n.1590C>G		non_coding_transcript_exon	Exon 13 of 13

Ensembl Transcripts

Sel.	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	Q13231-1
	CHIT1	ENST00000491855.5	TSL:1	n.*232C>G		non_coding_transcript_exon	Exon 12 of 12	ENSP00000423778.1	Q13231-2
	CHIT1	ENST00000503786.1	TSL:1	n.*467C>G		non_coding_transcript_exon	Exon 13 of 13	ENSP00000421617.1	D6REY1

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Chitotriosidase deficiency (2)
-	-	2	not provided (2)

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;