1-203216770-G-A

Variant names:

• chr1-203216770-G-A
• rs56391640
• NM_003465.3:c.*119C>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_003465.3(CHIT1):​c.*119C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00964 in 1,357,118 control chromosomes in the GnomAD database, including 88 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0071 (5 hom., cov: 33)
  • Exomes 𝑓: 0.010 (83 hom.)
• Consequence: CHIT1 NM_003465.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.829

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHIT1	NM_003465.3	c.*119C>T		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.*119C>T		3_prime_UTR_variant	Exon 11 of 11	1	NM_003465.3	ENSP00000356198.1

Frequencies

GnomAD3 genomes AF: 0.00715 AC: 1089 AN: 152222 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00203

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00798

Gnomad ASJ AF: 0.000579

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00372

Gnomad FIN AF: 0.00932

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0110

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00788 AC: 1824 AN: 231418 Hom.: 13 AF XY: 0.00789 AC XY: 1002 AN XY: 127058

Gnomad AFR exome AF: 0.00194

Gnomad AMR exome AF: 0.00935

Gnomad ASJ exome AF: 0.00115

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00493

Gnomad FIN exome AF: 0.00935

Gnomad NFE exome AF: 0.0108

Gnomad OTH exome AF: 0.00592

GnomAD4 exome AF: 0.00995 AC: 11988 AN: 1204778 Hom.: 83 Cov.: 17 AF XY: 0.00977 AC XY: 5975 AN XY: 611284

Gnomad4 AFR exome AF: 0.00169

Gnomad4 AMR exome AF: 0.00863

Gnomad4 ASJ exome AF: 0.00132

Gnomad4 EAS exome AF: 0.0000261

Gnomad4 SAS exome AF: 0.00515

Gnomad4 FIN exome AF: 0.0101

Gnomad4 NFE exome AF: 0.0116

Gnomad4 OTH exome AF: 0.00591

GnomAD4 genome AF: 0.00715 AC: 1089 AN: 152340 Hom.: 5 Cov.: 33 AF XY: 0.00675 AC XY: 503 AN XY: 74490

Gnomad4 AFR AF: 0.00202

Gnomad4 AMR AF: 0.00804

Gnomad4 ASJ AF: 0.000579

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.00932

Gnomad4 NFE AF: 0.0110

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00849 Hom.: 0

Bravo AF: 0.00640

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Chitotriosidase deficiency Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.0
DANN	Benign	0.38

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

Publications

LitVar

Other links and lift over

dbSNP: rs56391640; hg19: chr1-203185898;