Genetic Variant CTSA:c.-52G>A (chr20-45891274-G-A) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The ENST00000372484(CTSA):c.-52G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000424 in 1,508,190 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00045 ( 1 hom. )

Consequence

CTSA
ENST00000372484 5_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.269

Variant links:

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 links:

NEURL2 (HGNC:16156): (neuralized E3 ubiquitin protein ligase 2) This gene encodes a protein that is involved in the regulation of myofibril organization. This protein is likely the adaptor component of the E3 ubiquitin ligase complex in striated muscle, and it regulates the ubiquitin-mediated degradation of beta-catenin during myogenesis. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jun 2013]

NEURL2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.59).

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000454 (615/1355828) while in subpopulation NFE AF = 0.00058 (603/1040238). AF 95% confidence interval is 0.000541. There are 1 homozygotes in GnomAdExome4. There are 282 alleles in the male GnomAdExome4 subpopulation. Median coverage is 25. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTSA	NM_000308.4 link	c.-106G>A		upstream_gene_variant		ENST00000646241.3	NP_000299.3	P10619-1X6R8A1
NEURL2	NM_080749.4 link	c.-283C>T		upstream_gene_variant		ENST00000372518.5	NP_542787.1	Q9BR09

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTSA	ENST00000646241.3 link	c.-106G>A		upstream_gene_variant			NM_000308.4	ENSP00000493613.2		P10619-1
NEURL2	ENST00000372518.5 link	c.-283C>T		upstream_gene_variant		1	NM_080749.4	ENSP00000361596.4		Q9BR09

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000454

AC:

615

AN:

1355828

Hom.:

Cov.:

AF XY:

0.000420

AC XY:

282

AN XY:

671192

show subpopulations

Gnomad4 AFR exome

AF:

0.0000325

AC:

AN:

30754

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

35662

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

24934

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

35580

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

78280

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

48252

Gnomad4 NFE exome

AF:

0.000580

AC:

603

AN:

1040238

Gnomad4 Remaining exome

AF:

0.000194

AC:

AN:

56620

Heterozygous variant carriers

106

132

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000164

AC:

AN:

152362

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.0000962

AC:

0.0000961723

AN:

0.0000961723

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.000309

AC:

0.000308696

AN:

0.000308696

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.000181

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Combined deficiency of sialidase AND beta galactosidase

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

6.7

DANN

Benign

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over