rs9943208

Positions:

• chr1-203217835-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BA1

The ENST00000367229.6(CHIT1):​c.1060G>A​(p.Gly354Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00451 in 1,613,924 control chromosomes in the GnomAD database, including 268 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (133 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (135 hom.)
• Consequence: CHIT1 ENST00000367229.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: 7.10

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 -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.008951932).
• BP6: Variant 1-203217835-C-T is Benign according to our data. Variant chr1-203217835-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 472285.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-203217835-C-T is described in Lovd as [Benign].
• 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	c.1060G>A	p.Gly354Arg	missense_variant	10/11	ENST00000367229.6	NP_003456.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHIT1	ENST00000367229.6	c.1060G>A	p.Gly354Arg	missense_variant	10/11	1	NM_003465.3	ENSP00000356198	P1

Frequencies

GnomAD3 genomes AF: 0.0236 AC: 3591 AN: 152206 Hom.: 132 Cov.: 33

Gnomad AFR AF: 0.0817

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00903

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.00619 AC: 1547 AN: 250120 Hom.: 57 AF XY: 0.00437 AC XY: 591 AN XY: 135140

Gnomad AFR exome AF: 0.0832

Gnomad AMR exome AF: 0.00424

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000393

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000212

Gnomad OTH exome AF: 0.00295

GnomAD4 exome AF: 0.00251 AC: 3663 AN: 1461600 Hom.: 135 Cov.: 34 AF XY: 0.00224 AC XY: 1630 AN XY: 727084

Gnomad4 AFR exome AF: 0.0854

Gnomad4 AMR exome AF: 0.00483

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000476

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000143

Gnomad4 OTH exome AF: 0.00568

GnomAD4 genome AF: 0.0237 AC: 3611 AN: 152324 Hom.: 133 Cov.: 33 AF XY: 0.0222 AC XY: 1657 AN XY: 74492

Gnomad4 AFR AF: 0.0819

Gnomad4 AMR AF: 0.00901

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.00563 Hom.: 47

Bravo AF: 0.0273

ESP6500AA AF: 0.0783 AC: 345

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00763 AC: 926

EpiCase AF: 0.000109

EpiControl AF: 0.000416

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 16, 2015	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Chitotriosidase deficiency Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 18, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.096	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.50	D;.
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D
MetaRNN	Benign	0.0090	T;T
MetaSVM	Benign	-0.34	T
MutationAssessor	Pathogenic	4.8	H;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-7.1	D;D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.96
MutPred		0.91		Gain of MoRF binding (P = 0.0162);.;
MVP		0.97
MPC		0.54
ClinPred		0.11	T
GERP RS		3.8
Varity_R		0.98
gMVP		0.96

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: rs9943208; hg19: chr1-203186963;