rs3831317

Variant names:

• chr1-203217822-C-CAGACCATGGCCCCGCCCAGTCCCT
• rs3831317
• NM_003465.3:c.1049_1072dupAGGGACTGGGCGGGGCCATGGTCT

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BA1

The NM_003465.3(CHIT1):​c.1049_1072dupAGGGACTGGGCGGGGCCATGGTCT​(p.Val357_Trp358insTerGlyLeuGlyGlyAlaMetVal) variant causes a stop gained, conservative inframe insertion change. The variant allele was found at a frequency of 0.216 in 1,612,092 control chromosomes in the GnomAD database, including 43,887 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.18 (3446 hom., cov: 30)
  • Exomes 𝑓: 0.22 (40441 hom.)
• Consequence: CHIT1 NM_003465.3 stop_gained, conservative_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4 O:3
• Conservation: PhyloP100: 6.53
• Publications: 22 publications found

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

Our verdict: Benign. The variant received -14 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_003465.3.
• BP6: Variant 1-203217822-C-CAGACCATGGCCCCGCCCAGTCCCT is Benign according to our data. Variant chr1-203217822-C-CAGACCATGGCCCCGCCCAGTCCCT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 294920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.556 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003465.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHIT1	NM_003465.3	MANE Select	c.1049_1072dupAGGGACTGGGCGGGGCCATGGTCT	p.Val357_Trp358insTerGlyLeuGlyGlyAlaMetVal	stop_gained conservative_inframe_insertion	Exon 10 of 11	NP_003456.1	Q13231-1
	CHIT1	NM_001256125.2		c.992_1015dupAGGGACTGGGCGGGGCCATGGTCT	p.Val338_Trp339insTerGlyLeuGlyGlyAlaMetVal	stop_gained conservative_inframe_insertion	Exon 9 of 10	NP_001243054.2	Q13231-4
	CHIT1	NR_045784.2		n.1243_1266dupAGGGACTGGGCGGGGCCATGGTCT		non_coding_transcript_exon	Exon 11 of 13

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHIT1	ENST00000367229.6	TSL:1 MANE Select	c.1049_1072dupAGGGACTGGGCGGGGCCATGGTCT	p.Val357_Trp358insTerGlyLeuGlyGlyAlaMetVal	stop_gained conservative_inframe_insertion	Exon 10 of 11	ENSP00000356198.1	Q13231-1
	CHIT1	ENST00000491855.5	TSL:1	n.1049_1072dupAGGGACTGGGCGGGGCCATGGTCT		non_coding_transcript_exon	Exon 10 of 12	ENSP00000423778.1	Q13231-2
	CHIT1	ENST00000503786.1	TSL:1	n.*120_*143dupAGGGACTGGGCGGGGCCATGGTCT		non_coding_transcript_exon	Exon 11 of 13	ENSP00000421617.1	D6REY1

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27698 AN: 151884 Hom.: 3436 Cov.: 30

Gnomad AFR AF: 0.0541

Gnomad AMI AF: 0.132

Gnomad AMR AF: 0.259

Gnomad ASJ AF: 0.208

Gnomad EAS AF: 0.573

Gnomad SAS AF: 0.427

Gnomad FIN AF: 0.179

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.208

GnomAD4 exome AF: 0.220 AC: 321217 AN: 1460092 Hom.: 40441 Cov.: 34 AF XY: 0.225 AC XY: 163467 AN XY: 726266

African (AFR) AF: 0.0446 AC: 1494 AN: 33476

American (AMR) AF: 0.273 AC: 12179 AN: 44546

Ashkenazi Jewish (ASJ) AF: 0.217 AC: 5663 AN: 26106

East Asian (EAS) AF: 0.562 AC: 22264 AN: 39594

South Asian (SAS) AF: 0.396 AC: 34060 AN: 85974

European-Finnish (FIN) AF: 0.180 AC: 9614 AN: 53280

Middle Eastern (MID) AF: 0.242 AC: 1381 AN: 5696

European-Non Finnish (NFE) AF: 0.199 AC: 220970 AN: 1111106

Other (OTH) AF: 0.225 AC: 13592 AN: 60314

GnomAD4 genome AF: 0.182 AC: 27717 AN: 152000 Hom.: 3446 Cov.: 30 AF XY: 0.190 AC XY: 14127 AN XY: 74270

African (AFR) AF: 0.0539 AC: 2241 AN: 41546

American (AMR) AF: 0.261 AC: 3979 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.208 AC: 719 AN: 3464

East Asian (EAS) AF: 0.573 AC: 2926 AN: 5104

South Asian (SAS) AF: 0.428 AC: 2043 AN: 4778

European-Finnish (FIN) AF: 0.179 AC: 1899 AN: 10590

Middle Eastern (MID) AF: 0.238 AC: 70 AN: 294

European-Non Finnish (NFE) AF: 0.195 AC: 13279 AN: 67928

Other (OTH) AF: 0.209 AC: 441 AN: 2114

Alfa AF: 0.166 Hom.: 305

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Chitotriosidase deficiency (5)
-	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.5
Mutation Taster		=167/33	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs3831317; hg19: chr1-203186950; COSMIC: COSV55146605; COSMIC: COSV55146605;