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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, Illumina, G2P

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

Sel.	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	P10619-1
	CTSA	NM_001127695.3		c.948+7G>A		splice_region intron	N/A	NP_001121167.1	P10619-1
	CTSA	NM_001167594.3		c.897+7G>A		splice_region intron	N/A	NP_001161066.2	P10619-2

Ensembl Transcripts

Sel.	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	P10619-1
	CTSA	ENST00000372484.8	TSL:1	c.1002+7G>A		splice_region intron	N/A	ENSP00000361562.3	X6R8A1
	CTSA	ENST00000191018.9	TSL:1	c.948+7G>A		splice_region intron	N/A	ENSP00000191018.5	P10619-1

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Combined deficiency of sialidase AND beta galactosidase (3)
-	-	3	not provided (3)
-	-	1	not specified (1)

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;