rs2075961

Variant names:

• chr20-45894908-G-A
• rs2075961
• NM_000308.4:c.948+7G>A

Your query was ambiguous. Multiple possible variants found:

• chr20-45894908-G-A
• chr20-45894908-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• galactosialidosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, ClinGen, Illumina

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 338535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.71 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000308.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSA	NM_000308.4	MANE Select	c.948+7G>A		splice_region intron	N/A	NP_000299.3
	CTSA	NM_001127695.3		c.948+7G>A		splice_region intron	N/A	NP_001121167.1
	CTSA	NM_001167594.3		c.897+7G>A		splice_region intron	N/A	NP_001161066.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSA	ENST00000646241.3	MANE Select	c.948+7G>A		splice_region intron	N/A	ENSP00000493613.2
	CTSA	ENST00000372484.8	TSL:1	c.1002+7G>A		splice_region intron	N/A	ENSP00000361562.3
	CTSA	ENST00000191018.9	TSL:1	c.948+7G>A		splice_region intron	N/A	ENSP00000191018.5

Frequencies

GnomAD3 genomes AF: 0.656 AC: 99603 AN: 151776 Hom.: 32769 Cov.: 31

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

GnomAD2 exomes AF: 0.664 AC: 167046 AN: 251434 AF XY: 0.658

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 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

African (AFR) AF: 0.660 AC: 22087 AN: 33480

American (AMR) AF: 0.773 AC: 34578 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.522 AC: 13638 AN: 26132

East Asian (EAS) AF: 0.726 AC: 28836 AN: 39700

South Asian (SAS) AF: 0.677 AC: 58395 AN: 86256

European-Finnish (FIN) AF: 0.690 AC: 36851 AN: 53412

Middle Eastern (MID) AF: 0.580 AC: 3343 AN: 5768

European-Non Finnish (NFE) AF: 0.637 AC: 707916 AN: 1111972

Other (OTH) AF: 0.637 AC: 38470 AN: 60394

GnomAD4 genome AF: 0.656 AC: 99696 AN: 151894 Hom.: 32804 Cov.: 31 AF XY: 0.661 AC XY: 49014 AN XY: 74204

African (AFR) AF: 0.664 AC: 27502 AN: 41398

American (AMR) AF: 0.722 AC: 11004 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.534 AC: 1852 AN: 3470

East Asian (EAS) AF: 0.693 AC: 3573 AN: 5156

South Asian (SAS) AF: 0.680 AC: 3277 AN: 4822

European-Finnish (FIN) AF: 0.702 AC: 7387 AN: 10530

Middle Eastern (MID) AF: 0.602 AC: 177 AN: 294

European-Non Finnish (NFE) AF: 0.633 AC: 43022 AN: 67956

Other (OTH) AF: 0.645 AC: 1363 AN: 2112

Alfa AF: 0.633 Hom.: 13500

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

Submissions by phenotype

not provided Benign:3

Oct 19, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Combined deficiency of sialidase AND beta galactosidase Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.22
DANN	Benign	0.74
PhyloP100		-0.15
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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