1-111312237-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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, single submitter B:1
• Conservation: PhyloP100: -0.111

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

Verdict is Benign. Variant got -14 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 id is 769525.Status of the report is criteria_provided_single_submitter, 1 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHIA	NM_201653.4	c.103C>T	p.Arg35Trp	missense_variant	4/12	ENST00000369740.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHIA	ENST00000369740.6	c.103C>T	p.Arg35Trp	missense_variant	4/12	1	NM_201653.4	P1

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

GnomAD3 exomes AF: 0.00307 AC: 765 AN: 249344 Hom.: 15 AF XY: 0.00212 AC XY: 287 AN XY: 135274

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 SAS exome AF: 0.0000654

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

Gnomad4 AFR exome AF: 0.0464

Gnomad4 AMR exome AF: 0.00224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000387

Gnomad4 OTH exome AF: 0.00262

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

Gnomad4 AFR AF: 0.0437

Gnomad4 AMR AF: 0.00405

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.00401 Hom.: 8

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

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

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;T
Eigen	Benign	-0.017
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.27	N
MetaRNN	Benign	0.0059	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	0.97	D;D;D;D;D;D
PrimateAI	Benign	0.31	T
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Benign	0.21
Sift	Uncertain	0.016	D;D
Sift4G	Uncertain	0.016	D;D
Polyphen		0.90	P;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

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

Publications

LitVar

Other links and lift over

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