20-45891622-G-C

Variant names:

• chr20-45891622-G-C
• rs181943893
• NM_000308.4:c.54G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6 BP7

The NM_000308.4(CTSA):​c.54G>C​(p.Leu18Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000134 in 1,489,396 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L18del) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000071 (0 hom., cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: CTSA NM_000308.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 2.74
• Publications: 6 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 20-45891622-G-C is Benign according to our data. Variant chr20-45891622-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 459632.
• BP7: Synonymous conserved (PhyloP=2.74 with no splicing effect.

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.54G>C	p.Leu18Leu	synonymous	Exon 2 of 15	NP_000299.3
	CTSA	NM_001127695.3		c.54G>C	p.Leu18Leu	synonymous	Exon 2 of 15	NP_001121167.1
	CTSA	NM_001167594.3		c.54G>C	p.Leu18Leu	synonymous	Exon 2 of 14	NP_001161066.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTSA	ENST00000646241.3	MANE Select	c.54G>C	p.Leu18Leu	synonymous	Exon 2 of 15	ENSP00000493613.2
	CTSA	ENST00000372484.8	TSL:1	c.108G>C	p.Leu36Leu	synonymous	Exon 2 of 15	ENSP00000361562.3
	CTSA	ENST00000191018.9	TSL:1	c.54G>C	p.Leu18Leu	synonymous	Exon 2 of 15	ENSP00000191018.5

Frequencies

GnomAD3 genomes AF: 0.00000709 AC: 1 AN: 141032 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000268

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00164 AC: 388 AN: 237212 AF XY: 0.00141

Gnomad AFR exome AF: 0.000884

Gnomad AMR exome AF: 0.00350

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00848

Gnomad FIN exome AF: 0.00339

Gnomad NFE exome AF: 0.000140

Gnomad OTH exome AF: 0.000341

GnomAD4 exome AF: 7.42e-7 AC: 1 AN: 1348256 Hom.: 0 Cov.: 35 AF XY: 0.00000149 AC XY: 1 AN XY: 672514

African (AFR) AF: 0.00 AC: 0 AN: 29726

American (AMR) AF: 0.00 AC: 0 AN: 31302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24674

East Asian (EAS) AF: 0.0000342 AC: 1 AN: 29224

South Asian (SAS) AF: 0.00 AC: 0 AN: 76662

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5502

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1048584

Other (OTH) AF: 0.00 AC: 0 AN: 56028

GnomAD4 genome AF: 0.00000709 AC: 1 AN: 141140 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 68342

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 37946

American (AMR) AF: 0.00 AC: 0 AN: 13630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3388

East Asian (EAS) AF: 0.000268 AC: 1 AN: 3726

South Asian (SAS) AF: 0.00 AC: 0 AN: 4222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65754

Other (OTH) AF: 0.00 AC: 0 AN: 1984

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000114 Hom.: 0

Bravo AF: 0.0155

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	1	Combined deficiency of sialidase AND beta galactosidase (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	11
DANN	Benign	0.92
PhyloP100		2.7
PromoterAI		-0.0042	Neutral
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs181943893; hg19: chr20-44520261; COSMIC: COSV99509583; COSMIC: COSV99509583;