chr20-45895143-C-T

Position:

• chr20-45895143-C-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.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

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 20-45895143-C-T is Benign according to our data. Variant chr20-45895143-C-T is described in ClinVar as [Benign]. Clinvar id is 338538.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-45895143-C-T 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/exons	MANE	Protein	UniProt
CTSA	NM_000308.4	c.1088+10C>T		intron_variant		ENST00000646241.3	NP_000299.3
CTSA	NM_001127695.3	c.1088+10C>T		intron_variant			NP_001121167.1
CTSA	NM_001167594.3	c.1037+10C>T		intron_variant			NP_001161066.2
CTSA	NR_133656.2	n.1140+10C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTSA	ENST00000646241.3	c.1088+10C>T		intron_variant			NM_000308.4	ENSP00000493613

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

GnomAD3 exomes AF: 0.665 AC: 166930 AN: 251128 Hom.: 56111 AF XY: 0.659 AC XY: 89400 AN XY: 135732

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 SAS exome AF: 0.677

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

Gnomad4 AFR exome AF: 0.666

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

Gnomad4 AFR AF: 0.670

Gnomad4 AMR AF: 0.721

Gnomad4 ASJ AF: 0.533

Gnomad4 EAS AF: 0.694

Gnomad4 SAS AF: 0.681

Gnomad4 FIN AF: 0.702

Gnomad4 NFE AF: 0.633

Gnomad4 OTH AF: 0.645

Alfa AF: 0.633 Hom.: 53876

Bravo AF: 0.658

Asia WGS AF: 0.716 AC: 2490 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

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	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 19, 2015	- -

Combined deficiency of sialidase AND beta galactosidase Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	- -

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	4.3
DANN	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs4608591; hg19: chr20-44523782;