chr1-203217736-TACTC-T

Position:

chr1-203217736-TACTC-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PVS1_StrongBP6BA1

The ENST00000367229.6(CHIT1):c.1155_1156+2del variant causes a splice donor, coding sequence change. The variant allele was found at a frequency of 0.0045 in 1,613,672 control chromosomes in the GnomAD database, including 264 homozygotes. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L385L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.024 ( 129 hom., cov: 33)

Exomes 𝑓: 0.0025 ( 135 hom. )

Consequence

CHIT1
ENST00000367229.6 splice_donor, coding_sequence

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 3.60

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 made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates 0.17558886509635974 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.1, offset of 4, new splice context is: taaGTaagg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

BP6

Variant 1-203217736-TACTC-T is Benign according to our data. Variant chr1-203217736-TACTC-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 294917.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

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/exons	MANE	Protein	UniProt
CHIT1	NM_003465.3 linkuse as main transcript	c.1155_1156+2del		splice_donor_variant, coding_sequence_variant	10/11	ENST00000367229.6	NP_003456.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHIT1	ENST00000367229.6 linkuse as main transcript	c.1155_1156+2del		splice_donor_variant, coding_sequence_variant	10/11	1	NM_003465.3	ENSP00000356198	P1	Q13231-1

Frequencies

GnomAD3 genomes

AF:

0.0236

AC:

3586

AN:

151944

Hom.:

128

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0817

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00891

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000417

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000441

Gnomad OTH

AF:

0.0163

GnomAD3 exomes

AF:

0.00615

AC:

1545

AN:

251072

Hom.:

AF XY:

0.00436

AC XY:

591

AN XY:

135694

show subpopulations

Gnomad AFR exome

AF:

0.0833

Gnomad AMR exome

AF:

0.00431

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000168

Gnomad OTH exome

AF:

0.00294

GnomAD4 exome

AF:

0.00250

AC:

3648

AN:

1461610

Hom.:

135

AF XY:

0.00222

AC XY:

1616

AN XY:

727122

show subpopulations

Gnomad4 AFR exome

AF:

0.0854

Gnomad4 AMR exome

AF:

0.00485

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000301

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000140

Gnomad4 OTH exome

AF:

0.00570

GnomAD4 genome

AF:

0.0237

AC:

3606

AN:

152062

Hom.:

129

Cov.:

AF XY:

0.0222

AC XY:

1652

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.0819

Gnomad4 AMR

AF:

0.00890

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000417

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000441

Gnomad4 OTH

AF:

0.0166

Alfa

AF:

0.00336

Hom.:

Bravo

AF:

0.0273

Asia WGS

AF:

0.00577

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Chitotriosidase deficiency

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The CHIT1 c.1155_1156+2delGAGT variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. The variant has been reported in one study where CHIT1 genotyping of patients with Gaucher disease was performed to assess possible issues with therapeutic monitoring (Adelino et al. 2012). In this study, the c.1155_1156+2delGAGT variant was found in a one patient with Gaucher disease along with a second missense variant that is known to reduce chitotriosidase enzyme activity. It was noted that this patient also carried a common allele in this gene (duplication of 24 bp in exon 11 of the CHIT1 gene): an allele which is known to lead to an absence of chitotriosidase enzyme activity. The phase of these variants in this individual is unknown. Control data are unavailable for this variant, which is reported at a frequency of 0.12963 in the Yoruba Nigerian population of the 1000 Genomes Project. Based on the potential impact of splice variants and the limited evidence, the c.1155_1156+2delGAGT variant is classified as a variant of unknown significance but suspicious for pathogenicity for chitotriosidase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

not provided

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Dec 16, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.68

Position offset: -1

DS_DL_spliceai

1.0

Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over