NM_201653.4:c.103C>T

Variant names:

• chr1-111312237-C-T
• rs61752461
• NM_201653.4:c.103C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_201653.4(CHIA):​c.103C>T​(p.Arg35Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00234 in 1,614,084 control chromosomes in the GnomAD database, including 69 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R35Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (33 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (36 hom.)
• Consequence: CHIA NM_201653.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.111
• Publications: 3 publications found

Genes affected

CHIA (HGNC:17432): (chitinase acidic) The protein encoded by this gene degrades chitin, which is found in the cell wall of most fungi as well as in arthropods and some nematodes. The encoded protein can also stimulate interleukin 13 expression, and variations in this gene can lead to asthma susceptibility. Several transcript variants encoding a few different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0059217513).
• BP6: Variant 1-111312237-C-T is Benign according to our data. Variant chr1-111312237-C-T is described in ClinVar as Benign. ClinVar VariationId is 769525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0125 (1901/152254) while in subpopulation AFR AF = 0.0437 (1813/41520). AF 95% confidence interval is 0.042. There are 33 homozygotes in GnomAd4. There are 861 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_201653.4. 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
	CHIA	NM_201653.4	MANE Select	c.103C>T	p.Arg35Trp	missense	Exon 4 of 12	NP_970615.2	Q9BZP6-1
	CHIA	NM_001258001.2		c.-68+519C>T		intron	N/A	NP_001244930.1	Q9BZP6-2
	CHIA	NM_001258003.2		c.-68+519C>T		intron	N/A	NP_001244932.1	Q9BZP6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHIA	ENST00000369740.6	TSL:1 MANE Select	c.103C>T	p.Arg35Trp	missense	Exon 4 of 12	ENSP00000358755.1	Q9BZP6-1
	CHIA	ENST00000422815.5	TSL:1	c.90-2303C>T		intron	N/A	ENSP00000387671.1	Q5VUV5
	CHIA	ENST00000430615.1	TSL:1	c.-68+519C>T		intron	N/A	ENSP00000391132.1	Q9BZP6-2

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1893 AN: 152136 Hom.: 33 Cov.: 31

Gnomad AFR AF: 0.0436

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00307 AC: 765 AN: 249344 AF XY: 0.00212

Gnomad AFR exome AF: 0.0431

Gnomad AMR exome AF: 0.00209

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00128 AC: 1878 AN: 1461830 Hom.: 36 Cov.: 33 AF XY: 0.00110 AC XY: 801 AN XY: 727226

African (AFR) AF: 0.0464 AC: 1553 AN: 33472

American (AMR) AF: 0.00224 AC: 100 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39698

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.0000387 AC: 43 AN: 1111966

Other (OTH) AF: 0.00262 AC: 158 AN: 60394

GnomAD4 genome AF: 0.0125 AC: 1901 AN: 152254 Hom.: 33 Cov.: 31 AF XY: 0.0116 AC XY: 861 AN XY: 74442

African (AFR) AF: 0.0437 AC: 1813 AN: 41520

American (AMR) AF: 0.00405 AC: 62 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68024

Other (OTH) AF: 0.00805 AC: 17 AN: 2112

Alfa AF: 0.00809 Hom.: 26

Bravo AF: 0.0146

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0406 AC: 170

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00357 AC: 432

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.017
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.27	N
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		-0.11
PrimateAI	Benign	0.31	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Benign	0.21
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.016	D
Polyphen		0.90	P
Vest4		0.67
MVP		0.45
MPC		0.12
ClinPred		0.086	T
GERP RS		-0.17
Varity_R		0.78
gMVP		0.89
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs61752461; hg19: chr1-111854859; COSMIC: COSV99056565;