rs2075961

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000308.4(CTSA):​c.948+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 1,613,730 control chromosomes in the GnomAD database, including 338,948 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.66 ( 32804 hom., cov: 31)
Exomes 𝑓: 0.65 ( 306144 hom. )

Consequence

CTSA
NM_000308.4 splice_region, intron

Scores

2
Splicing: ADA: 0.00002833
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.153
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.86).
BP6
Variant 20-45894908-G-A is Benign according to our data. Variant chr20-45894908-G-A is described in ClinVar as [Benign]. Clinvar id is 338535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-45894908-G-A is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.71 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CTSANM_000308.4 linkuse as main transcriptc.948+7G>A splice_region_variant, intron_variant ENST00000646241.3 NP_000299.3 P10619-1X6R8A1
CTSANM_001127695.3 linkuse as main transcriptc.948+7G>A splice_region_variant, intron_variant NP_001121167.1 P10619-1
CTSANM_001167594.3 linkuse as main transcriptc.897+7G>A splice_region_variant, intron_variant NP_001161066.2 P10619-2B4E324X6R5C5
CTSANR_133656.2 linkuse as main transcriptn.1000+7G>A splice_region_variant, intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CTSAENST00000646241.3 linkuse as main transcriptc.948+7G>A splice_region_variant, intron_variant NM_000308.4 ENSP00000493613.2 P10619-1

Frequencies

GnomAD3 genomes
AF:
0.656
AC:
99603
AN:
151776
Hom.:
32769
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.664
Gnomad AMI
AF:
0.594
Gnomad AMR
AF:
0.721
Gnomad ASJ
AF:
0.534
Gnomad EAS
AF:
0.693
Gnomad SAS
AF:
0.679
Gnomad FIN
AF:
0.702
Gnomad MID
AF:
0.592
Gnomad NFE
AF:
0.633
Gnomad OTH
AF:
0.643
GnomAD3 exomes
AF:
0.664
AC:
167046
AN:
251434
Hom.:
56127
AF XY:
0.658
AC XY:
89469
AN XY:
135900
show subpopulations
Gnomad AFR exome
AF:
0.664
Gnomad AMR exome
AF:
0.779
Gnomad ASJ exome
AF:
0.512
Gnomad EAS exome
AF:
0.690
Gnomad SAS exome
AF:
0.676
Gnomad FIN exome
AF:
0.690
Gnomad NFE exome
AF:
0.632
Gnomad OTH exome
AF:
0.645
GnomAD4 exome
AF:
0.646
AC:
944114
AN:
1461836
Hom.:
306144
Cov.:
62
AF XY:
0.645
AC XY:
469373
AN XY:
727228
show subpopulations
Gnomad4 AFR exome
AF:
0.660
Gnomad4 AMR exome
AF:
0.773
Gnomad4 ASJ exome
AF:
0.522
Gnomad4 EAS exome
AF:
0.726
Gnomad4 SAS exome
AF:
0.677
Gnomad4 FIN exome
AF:
0.690
Gnomad4 NFE exome
AF:
0.637
Gnomad4 OTH exome
AF:
0.637
GnomAD4 genome
AF:
0.656
AC:
99696
AN:
151894
Hom.:
32804
Cov.:
31
AF XY:
0.661
AC XY:
49014
AN XY:
74204
show subpopulations
Gnomad4 AFR
AF:
0.664
Gnomad4 AMR
AF:
0.722
Gnomad4 ASJ
AF:
0.534
Gnomad4 EAS
AF:
0.693
Gnomad4 SAS
AF:
0.680
Gnomad4 FIN
AF:
0.702
Gnomad4 NFE
AF:
0.633
Gnomad4 OTH
AF:
0.645
Alfa
AF:
0.632
Hom.:
13328
Bravo
AF:
0.656
Asia WGS
AF:
0.715
AC:
2488
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Benign, no assertion criteria providedclinical testingMayo Clinic Laboratories, Mayo ClinicOct 19, 2015- -
Benign, criteria provided, single submitterclinical testingGeneDxJun 19, 2018This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Combined deficiency of sialidase AND beta galactosidase Benign:3
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 30, 2021- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 01, 2024- -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 28, 2016Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 66% of total chromosomes in ExAC -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.86
CADD
Benign
0.22
DANN
Benign
0.74

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000028
dbscSNV1_RF
Benign
0.048
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2075961; hg19: chr20-44523547; COSMIC: COSV51943002; COSMIC: COSV51943002; API