rs137852607

Positions:

• chr1-203225706-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_003465.3(CHIT1):​c.220G>A​(p.Glu74Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0044 in 1,613,996 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. E74G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0034 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0045 (24 hom.)
• Consequence: CHIT1 NM_003465.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1 O:1
• Conservation: PhyloP100: 0.709

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.040317446).
• BP6: Variant 1-203225706-C-T is Benign according to our data. Variant chr1-203225706-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 9525.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHIT1	NM_003465.3	c.220G>A	p.Glu74Lys	missense_variant	3/11	ENST00000367229.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHIT1	ENST00000367229.6	c.220G>A	p.Glu74Lys	missense_variant	3/11	1	NM_003465.3	P1

Frequencies

GnomAD3 genomes AF: 0.00344 AC: 523 AN: 152096 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00786

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00283

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00384

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00342 AC: 860 AN: 251470 Hom.: 1 AF XY: 0.00347 AC XY: 471 AN XY: 135906

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00321

Gnomad ASJ exome AF: 0.0122

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00265

Gnomad FIN exome AF: 0.00254

Gnomad NFE exome AF: 0.00395

Gnomad OTH exome AF: 0.00407

GnomAD4 exome AF: 0.00450 AC: 6582 AN: 1461782 Hom.: 24 Cov.: 35 AF XY: 0.00437 AC XY: 3179 AN XY: 727188

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.00360

Gnomad4 ASJ exome AF: 0.0124

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00264

Gnomad4 FIN exome AF: 0.00311

Gnomad4 NFE exome AF: 0.00482

Gnomad4 OTH exome AF: 0.00515

GnomAD4 genome AF: 0.00344 AC: 523 AN: 152214 Hom.: 2 Cov.: 31 AF XY: 0.00312 AC XY: 232 AN XY: 74414

Gnomad4 AFR AF: 0.00104

Gnomad4 AMR AF: 0.00785

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00283

Gnomad4 NFE AF: 0.00384

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00416 Hom.: 0

Bravo AF: 0.00360

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00571 AC: 22

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00465 AC: 40

ExAC AF: 0.00320 AC: 389

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00474

EpiControl AF: 0.00468

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Chitotriosidase deficiency Uncertain:1 Benign:1 Other:1

Uncertain significance, 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Aug 09, 2019	- -
Affects, no assertion criteria provided	literature only	OMIM	Sep 01, 2007	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	8.9
DANN	Benign	0.70
DEOGEN2	Benign	0.25	T;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.040	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	9.7e-7	A;A;A
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.28
Sift	Benign	0.37	T;T
Sift4G	Benign	0.76	T;T
Polyphen		0.062	B;.
Vest4		0.67
MVP		0.25
MPC		0.11
ClinPred		0.0054	T
GERP RS		0.79
Varity_R		0.27
gMVP		0.49

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: rs137852607; hg19: chr1-203194834;