Genetic Variant NM_005213.4:c.67-414C>T (chr3-122337133-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005213.4(CSTA):c.67-414C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 152,010 control chromosomes in the GnomAD database, including 1,775 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.14 ( 1775 hom., cov: 32)

Consequence

CSTA
NM_005213.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.103

Publications

4 publications found

Variant links:

Genes affected

CSTA (HGNC:2481): (cystatin A) The cystatin superfamily encompasses proteins that contain multiple cystatin-like sequences. Some of the members are active cysteine protease inhibitors, while others have lost or perhaps never acquired this inhibitory activity. There are three inhibitory families in the superfamily, including the type 1 cystatins (stefins), type 2 cystatins, and kininogens. This gene encodes a stefin that functions as a cysteine protease inhibitor, forming tight complexes with papain and the cathepsins B, H, and L. The protein is one of the precursor proteins of cornified cell envelope in keratinocytes and plays a role in epidermal development and maintenance. Stefins have been proposed as prognostic and diagnostic tools for cancer. [provided by RefSeq, Jul 2008]

CSTA Gene-Disease associations (from GenCC):

peeling skin syndrome 4
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, PanelApp Australia, G2P, Labcorp Genetics (formerly Invitae)
acral peeling skin syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
exfoliative ichthyosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CSTA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.0).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.424 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSTA	NM_005213.4 link	c.67-414C>T		intron_variant	Intron 1 of 2	ENST00000264474.4	NP_005204.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSTA	ENST00000264474.4 link	c.67-414C>T		intron_variant	Intron 1 of 2	1	NM_005213.4	ENSP00000264474.3
CSTA	ENST00000479204.1 link	c.67-414C>T		intron_variant	Intron 1 of 1	2		ENSP00000418891.1

Frequencies

GnomAD3 genomes

AF:

0.135

AC:

20556

AN:

151892

Hom.:

1777

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0719

Gnomad AMI

AF:

0.405

Gnomad AMR

AF:

0.109

Gnomad ASJ

AF:

0.119

Gnomad EAS

AF:

0.439

Gnomad SAS

AF:

0.101

Gnomad FIN

AF:

0.140

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.156

Gnomad OTH

AF:

0.140

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.135

AC:

20548

AN:

152010

Hom.:

1775

Cov.:

AF XY:

0.136

AC XY:

10070

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.0717

AC:

2976

AN:

41478

American (AMR)

AF:

0.109

AC:

1662

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.119

AC:

412

AN:

3472

East Asian (EAS)

AF:

0.439

AC:

2268

AN:

5170

South Asian (SAS)

AF:

0.100

AC:

483

AN:

4820

European-Finnish (FIN)

AF:

0.140

AC:

1470

AN:

10526

Middle Eastern (MID)

AF:

0.119

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.156

AC:

10577

AN:

67962

Other (OTH)

AF:

0.141

AC:

297

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

897

1793

2690

3586

4483

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

220

440

660

880

1100

<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:

0.143

Hom.:

1202

Bravo

AF:

0.134

Asia WGS

AF:

0.217

AC:

754

AN:

3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

4.8

(source)

DANN

Benign

0.48

PhyloP100

-0.10

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over