1-203216355-A-C

Variant names:

• chr1-203216355-A-C
• rs73066394
• NM_003465.3:c.*534T>G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003465.3(CHIT1):​c.*534T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0284 in 454,014 control chromosomes in the GnomAD database, including 1,293 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.066 (1083 hom., cov: 33)
  • Exomes 𝑓: 0.0096 (210 hom.)
• Consequence: CHIT1 NM_003465.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.972

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 1-203216355-A-C is Benign according to our data. Variant chr1-203216355-A-C is described in ClinVar as [Benign]. Clinvar id is 294902.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.221 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHIT1	NM_003465.3	c.*534T>G		3_prime_UTR_variant	Exon 11 of 11	ENST00000367229.6	NP_003456.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHIT1	ENST00000367229	c.*534T>G		3_prime_UTR_variant	Exon 11 of 11	1	NM_003465.3	ENSP00000356198.1
CHIT1	ENST00000479483.1	n.283+1384T>G		intron_variant	Intron 1 of 1	3
CHIT1	ENST00000484834.5	n.5388+1384T>G		intron_variant	Intron 11 of 11	2

Frequencies

GnomAD3 genomes AF: 0.0655 AC: 9959 AN: 152088 Hom.: 1075 Cov.: 33

Gnomad AFR AF: 0.224

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0288

Gnomad ASJ AF: 0.00951

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00126

Gnomad OTH AF: 0.0588

GnomAD3 exomes AF: 0.0154 AC: 2003 AN: 130214 Hom.: 145 AF XY: 0.0120 AC XY: 854 AN XY: 71096

Gnomad AFR exome AF: 0.232

Gnomad AMR exome AF: 0.0161

Gnomad ASJ exome AF: 0.0100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000670

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00123

Gnomad OTH exome AF: 0.00999

GnomAD4 exome AF: 0.00958 AC: 2892 AN: 301808 Hom.: 210 Cov.: 0 AF XY: 0.00723 AC XY: 1243 AN XY: 172006

Gnomad4 AFR exome AF: 0.226

Gnomad4 AMR exome AF: 0.0157

Gnomad4 ASJ exome AF: 0.00955

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000821

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000655

Gnomad4 OTH exome AF: 0.0178

GnomAD4 genome AF: 0.0657 AC: 10002 AN: 152206 Hom.: 1083 Cov.: 33 AF XY: 0.0633 AC XY: 4715 AN XY: 74432

Gnomad4 AFR AF: 0.224

Gnomad4 AMR AF: 0.0288

Gnomad4 ASJ AF: 0.00951

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00126

Gnomad4 OTH AF: 0.0587

Alfa AF: 0.0400 Hom.: 154

Bravo AF: 0.0753

Asia WGS AF: 0.0140 AC: 51 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Chitotriosidase deficiency Benign:1

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.51
DANN	Benign	0.41

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

LitVar

Other links and lift over

dbSNP: rs73066394; hg19: chr1-203185483;