rs4608591

Variant names:

• chr20-45895143-C-T
• rs4608591
• NM_000308.4:c.1088+10C>T

Your query was ambiguous. Multiple possible variants found:

• chr20-45895143-C-T
• chr20-45895143-C-A

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.1088+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 1,613,544 control chromosomes in the GnomAD database, including 339,194 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.66 (32954 hom., cov: 30)
  • Exomes 𝑓: 0.65 (306240 hom.)
• Consequence: CTSA NM_000308.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.592
• Publications: 23 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 20-45895143-C-T is Benign according to our data. Variant chr20-45895143-C-T is described in ClinVar as Benign. ClinVar VariationId is 338538.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.1088+10C>T		intron	N/A	NP_000299.3	P10619-1
	CTSA	NM_001127695.3		c.1088+10C>T		intron	N/A	NP_001121167.1	P10619-1
	CTSA	NM_001167594.3		c.1037+10C>T		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.1088+10C>T		intron	N/A	ENSP00000493613.2	P10619-1
	CTSA	ENST00000372484.8	TSL:1	c.1142+10C>T		intron	N/A	ENSP00000361562.3	X6R8A1
	CTSA	ENST00000191018.9	TSL:1	c.1088+10C>T		intron	N/A	ENSP00000191018.5	P10619-1

Frequencies

GnomAD3 genomes AF: 0.658 AC: 99810 AN: 151726 Hom.: 32919 Cov.: 30

Gnomad AFR AF: 0.670

Gnomad AMI AF: 0.592

Gnomad AMR AF: 0.721

Gnomad ASJ AF: 0.533

Gnomad EAS AF: 0.694

Gnomad SAS AF: 0.681

Gnomad FIN AF: 0.702

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.633

Gnomad OTH AF: 0.642

GnomAD2 exomes AF: 0.665 AC: 166930 AN: 251128 AF XY: 0.659

Gnomad AFR exome AF: 0.669

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: 0.644

GnomAD4 exome AF: 0.646 AC: 944208 AN: 1461700 Hom.: 306240 Cov.: 58 AF XY: 0.646 AC XY: 469418 AN XY: 727142

African (AFR) AF: 0.666 AC: 22301 AN: 33476

American (AMR) AF: 0.773 AC: 34561 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.522 AC: 13629 AN: 26134

East Asian (EAS) AF: 0.726 AC: 28837 AN: 39696

South Asian (SAS) AF: 0.677 AC: 58425 AN: 86254

European-Finnish (FIN) AF: 0.690 AC: 36808 AN: 53352

Middle Eastern (MID) AF: 0.580 AC: 3345 AN: 5768

European-Non Finnish (NFE) AF: 0.637 AC: 707828 AN: 1111912

Other (OTH) AF: 0.637 AC: 38474 AN: 60386

GnomAD4 genome AF: 0.658 AC: 99903 AN: 151844 Hom.: 32954 Cov.: 30 AF XY: 0.662 AC XY: 49110 AN XY: 74200

African (AFR) AF: 0.670 AC: 27718 AN: 41388

American (AMR) AF: 0.721 AC: 10998 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.533 AC: 1851 AN: 3470

East Asian (EAS) AF: 0.694 AC: 3572 AN: 5150

South Asian (SAS) AF: 0.681 AC: 3280 AN: 4814

European-Finnish (FIN) AF: 0.702 AC: 7390 AN: 10534

Middle Eastern (MID) AF: 0.599 AC: 175 AN: 292

European-Non Finnish (NFE) AF: 0.633 AC: 43018 AN: 67930

Other (OTH) AF: 0.645 AC: 1362 AN: 2112

Alfa AF: 0.640 Hom.: 82454

Bravo AF: 0.658

Asia WGS AF: 0.716 AC: 2490 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	4.3
DANN	Benign	0.60
PhyloP100		-0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs4608591; hg19: chr20-44523782; COSMIC: COSV107206972; COSMIC: COSV107206972;