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. Variant got -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

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=-0.86).
• 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 rank	MANE	Protein	UniProt
CTSA	NM_000308.4	c.948+7G>A		splice_region_variant, intron_variant	Intron 10 of 14	ENST00000646241.3	NP_000299.3
CTSA	NM_001127695.3	c.948+7G>A		splice_region_variant, intron_variant	Intron 10 of 14		NP_001121167.1
CTSA	NM_001167594.3	c.897+7G>A		splice_region_variant, intron_variant	Intron 9 of 13		NP_001161066.2
CTSA	NR_133656.2	n.1000+7G>A		splice_region_variant, intron_variant	Intron 10 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSA	ENST00000646241.3	c.948+7G>A		splice_region_variant, intron_variant	Intron 10 of 14		NM_000308.4	ENSP00000493613.2

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

GnomAD3 exomes AF: 0.664 AC: 167046 AN: 251434 Hom.: 56127 AF XY: 0.658 AC XY: 89469 AN XY: 135900

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

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

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

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

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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 v4.3

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

Other links and lift over

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