Genetic Variant NM_005213.4:c.66+4439A>G (chr3-122329797-A-G) – 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.66+4439A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 152,278 control chromosomes in the GnomAD database, including 1,406 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 0.12 ( 1406 hom., cov: 32)

Consequence

CSTA
NM_005213.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.05

Publications

32 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=-0.86).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSTA	NM_005213.4 link	c.66+4439A>G		intron_variant	Intron 1 of 2	ENST00000264474.4	NP_005204.1	P01040

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSTA	ENST00000264474.4 link	c.66+4439A>G		intron_variant	Intron 1 of 2	1	NM_005213.4	ENSP00000264474.3		P01040
CSTA	ENST00000479204.1 link	c.66+4439A>G		intron_variant	Intron 1 of 1	2		ENSP00000418891.1		C9J0E4

Frequencies

GnomAD3 genomes

AF:

0.121

AC:

18426

AN:

152160

Hom.:

1405

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0431

Gnomad AMI

AF:

0.116

Gnomad AMR

AF:

0.141

Gnomad ASJ

AF:

0.283

Gnomad EAS

AF:

0.0281

Gnomad SAS

AF:

0.185

Gnomad FIN

AF:

0.140

Gnomad MID

AF:

0.263

Gnomad NFE

AF:

0.154

Gnomad OTH

AF:

0.159

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

GnomAD4 genome

AF:

0.121

AC:

18424

AN:

152278

Hom.:

1406

Cov.:

AF XY:

0.121

AC XY:

9045

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0431

AC:

1792

AN:

41570

American (AMR)

AF:

0.141

AC:

2159

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.283

AC:

981

AN:

3470

East Asian (EAS)

AF:

0.0277

AC:

144

AN:

5190

South Asian (SAS)

AF:

0.185

AC:

894

AN:

4828

European-Finnish (FIN)

AF:

0.140

AC:

1485

AN:

10598

Middle Eastern (MID)

AF:

0.265

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.154

AC:

10454

AN:

68008

Other (OTH)

AF:

0.157

AC:

331

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

830

1660

2490

3320

4150

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

216

432

648

864

1080

<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:

0.139

Hom.:

2665

Bravo

AF:

0.117

Asia WGS

AF:

0.113

AC:

395

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

8.2

(source)

DANN

Benign

0.42

PhyloP100

1.0

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