1-203216939-G-A

Position:

chr1-203216939-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_003465.3(CHIT1):c.1351C>T(p.Pro451Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00068 in 1,614,228 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P451R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00082 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00067 ( 8 hom. )

Consequence

CHIT1
NM_003465.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.18

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 Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0063231587).

BP6

Variant 1-203216939-G-A is Benign according to our data. Variant chr1-203216939-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 294909.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.

BS2

High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHIT1	NM_003465.3 linkuse as main transcript	c.1351C>T	p.Pro451Ser	missense_variant	11/11	ENST00000367229.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHIT1	ENST00000367229.6 linkuse as main transcript	c.1351C>T	p.Pro451Ser	missense_variant	11/11	1	NM_003465.3	P1	Q13231-1

Frequencies

GnomAD3 genomes

AF:

0.000821

AC:

125

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00281

Gnomad ASJ

AF:

0.0135

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000928

AC:

233

AN:

251156

Hom.:

AF XY:

0.000921

AC XY:

125

AN XY:

135756

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.0116

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000493

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.000666

AC:

973

AN:

1461878

Hom.:

Cov.:

AF XY:

0.000656

AC XY:

477

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00145

Gnomad4 ASJ exome

AF:

0.0131

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000411

Gnomad4 OTH exome

AF:

0.00162

GnomAD4 genome

AF:

0.000820

AC:

125

AN:

152350

Hom.:

Cov.:

AF XY:

0.000738

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.00281

Gnomad4 ASJ

AF:

0.0135

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00113

Hom.:

Bravo

AF:

0.00135

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000708

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000415

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

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	- -

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

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.28

T;.

Eigen

Benign

0.016

Eigen_PC

Benign

-0.098

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.54

T;T

M_CAP

Benign

0.024

MetaRNN

Benign

0.0063

T;T

MetaSVM

Benign

-0.66

MutationAssessor

Pathogenic

2.9

M;.

MutationTaster

Benign

0.94

D;D;D

PrimateAI

Benign

0.30

PROVEAN

Uncertain

-2.6

D;D

REVEL

Benign

0.20

Sift

Benign

0.26

T;T

Sift4G

Benign

0.23

T;T

Polyphen

0.99

D;.

Vest4

0.21

MVP

0.61

MPC

0.46

ClinPred

0.083

GERP RS

4.0

Varity_R

0.34

gMVP

0.67

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

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