rs2075961

Positions:

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

Splicing: ADA: 0.00002833

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]

CTSA links:

CTSA (HGNC:):

CTSA links:

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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	Effect	MANE	Protein	UniProt
CTSA	NM_000308.4 linkuse as main transcript	c.948+7G>A	splice_region_variant, intron_variant	ENST00000646241.3	NP_000299.3	P10619-1X6R8A1
CTSA	NM_001127695.3 linkuse as main transcript	c.948+7G>A	splice_region_variant, intron_variant		NP_001121167.1	P10619-1
CTSA	NM_001167594.3 linkuse as main transcript	c.897+7G>A	splice_region_variant, intron_variant		NP_001161066.2	P10619-2B4E324X6R5C5
CTSA	NR_133656.2 linkuse as main transcript	n.1000+7G>A	splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSA	ENST00000646241.3 linkuse as main transcript	c.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.:

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.:

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.:

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 provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 19, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2018	This 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 submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Combined deficiency of sialidase AND beta galactosidase

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This 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 submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant 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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over