20-45891283-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000372484.8(CTSA):c.-43G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00951 in 1,522,640 control chromosomes in the GnomAD database, including 696 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (66 hom., cov: 33)
  • Exomes 𝑓: 0.0090 (630 hom.)
• Consequence: CTSA ENST00000372484.8 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -0.315

Genes affected

CTSA (HGNC:9251): (cathepsin A) This gene encodes a member of the peptidase S10 family of serine carboxypeptidases. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate two chains that comprise the heterodimeric active enzyme. This enzyme possesses deamidase, esterase and carboxypeptidase activities and acts as a scaffold in the lysosomal multienzyme complex. Mutations in this gene are associated with galactosialidosis. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 20-45891283-G-T is Benign according to our data. Variant chr20-45891283-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 338522.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.116 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSA	ENST00000372484.8	c.-43G>T		5_prime_UTR_variant	1/15	1		P1
CTSA	ENST00000677394.1	c.-43G>T		5_prime_UTR_variant	2/16			P1
CTSA	ENST00000480961.3	n.321G>T		non_coding_transcript_exon_variant	1/10	2

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2128 AN: 152218 Hom.: 66 Cov.: 33

Gnomad AFR AF: 0.0128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0254

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.0362

Gnomad FIN AF: 0.0277

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00101

Gnomad OTH AF: 0.00957

GnomAD3 exomes AF: 0.0277 AC: 4251 AN: 153190 Hom.: 198 AF XY: 0.0254 AC XY: 2079 AN XY: 81808

Gnomad AFR exome AF: 0.0128

Gnomad AMR exome AF: 0.0701

Gnomad ASJ exome AF: 0.000947

Gnomad EAS exome AF: 0.116

Gnomad SAS exome AF: 0.0283

Gnomad FIN exome AF: 0.0240

Gnomad NFE exome AF: 0.000696

Gnomad OTH exome AF: 0.0191

GnomAD4 exome AF: 0.00902 AC: 12355 AN: 1370304 Hom.: 630 Cov.: 27 AF XY: 0.00934 AC XY: 6327 AN XY: 677526

Gnomad4 AFR exome AF: 0.0122

Gnomad4 AMR exome AF: 0.0624

Gnomad4 ASJ exome AF: 0.000800

Gnomad4 EAS exome AF: 0.145

Gnomad4 SAS exome AF: 0.0290

Gnomad4 FIN exome AF: 0.0196

Gnomad4 NFE exome AF: 0.000558

Gnomad4 OTH exome AF: 0.0128

GnomAD4 genome AF: 0.0139 AC: 2124 AN: 152336 Hom.: 66 Cov.: 33 AF XY: 0.0163 AC XY: 1211 AN XY: 74480

Gnomad4 AFR AF: 0.0127

Gnomad4 AMR AF: 0.0254

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.124

Gnomad4 SAS AF: 0.0362

Gnomad4 FIN AF: 0.0277

Gnomad4 NFE AF: 0.00101

Gnomad4 OTH AF: 0.00947

Alfa AF: 0.00231 Hom.: 1

Bravo AF: 0.0155

Asia WGS AF: 0.0780 AC: 270 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1 Other:1

not provided, no classification provided	in vitro	Seelig Lab, University of Washington	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2019	- -

Combined deficiency of sialidase AND beta galactosidase Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	2.6
Dann	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs116893852; hg19: chr20-44519922; COSMIC: COSV51942787; COSMIC: COSV51942787;