1-22001684-C-T

Variant names:

• chr1-22001684-C-T
• rs143304998
• NM_005747.5:c.10C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005747.5(CELA3A):​c.10C>T​(p.Arg4Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000844 in 1,612,146 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00017 (1 hom., cov: 31)
  • Exomes 𝑓: 0.000076 (1 hom.)
• Consequence: CELA3A NM_005747.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.441

Genes affected

CELA3A (HGNC:15944): (chymotrypsin like elastase 3A) Elastases form a subfamily of serine proteases that hydrolyze many proteins in addition to elastin. Humans have six elastase genes which encode the structurally similar proteins elastase 1, 2, 2A, 2B, 3A, and 3B. Unlike other elastases, elastase 3A has little elastolytic activity. Like most of the human elastases, elastase 3A is secreted from the pancreas as a zymogen and, like other serine proteases such as trypsin, chymotrypsin and kallikrein, it has a digestive function in the intestine. Elastase 3A preferentially cleaves proteins after alanine residues. Elastase 3A may also function in the intestinal transport and metabolism of cholesterol. Both elastase 3A and elastase 3B have been referred to as protease E and as elastase 1. [provided by RefSeq, Jul 2008]

ENSG00000285959 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.063944876).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CELA3A	NM_005747.5	c.10C>T	p.Arg4Trp	missense_variant	Exon 1 of 8	ENST00000290122.8	NP_005738.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CELA3A	ENST00000290122.8	c.10C>T	p.Arg4Trp	missense_variant	Exon 1 of 8	1	NM_005747.5	ENSP00000290122.3
CELA3A	ENST00000374663.1	n.25C>T		non_coding_transcript_exon_variant	Exon 1 of 4	2
ENSG00000285959	ENST00000650360.1	n.522-3763C>T		intron_variant	Intron 3 of 8

Frequencies

GnomAD3 genomes AF: 0.000166 AC: 25 AN: 150986 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000344

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000198

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000975

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000481

GnomAD3 exomes AF: 0.000207 AC: 52 AN: 251308 Hom.: 2 AF XY: 0.000214 AC XY: 29 AN XY: 135822

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000654

Gnomad SAS exome AF: 0.00118

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000760 AC: 111 AN: 1461042 Hom.: 1 Cov.: 31 AF XY: 0.0000908 AC XY: 66 AN XY: 726822

Gnomad4 AFR exome AF: 0.000330

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000228

Gnomad4 SAS exome AF: 0.000835

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.000165 AC: 25 AN: 151104 Hom.: 1 Cov.: 31 AF XY: 0.000122 AC XY: 9 AN XY: 73844

Gnomad4 AFR AF: 0.000343

Gnomad4 AMR AF: 0.000198

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000977

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000476

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.000219

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000189 AC: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.10C>T (p.R4W) alteration is located in exon 1 (coding exon 1) of the CELA3A gene. This alteration results from a C to T substitution at nucleotide position 10, causing the arginine (R) at amino acid position 4 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.064	T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	0.69	N
PROVEAN	Uncertain	-2.9	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.021	D
Sift4G	Benign	0.18	T
Polyphen		0.99	D
Vest4		0.29
MVP		0.70
MPC		0.086
ClinPred		0.12	T
GERP RS		1.2
Varity_R		0.090
gMVP		0.68

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: rs143304998; hg19: chr1-22328177; COSMIC: COSV51585337; COSMIC: COSV51585337;