3-122341427-A-C

Position:

• chr3-122341427-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005213.4(CSTA):​c.169-12A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0521 in 1,613,030 control chromosomes in the GnomAD database, including 3,096 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (831 hom., cov: 31)
  • Exomes 𝑓: 0.049 (2265 hom.)
• Consequence: CSTA NM_005213.4 intron
• Scores: Splicing: ADA: 0.00003954
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.82

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 3-122341427-A-C is Benign according to our data. Variant chr3-122341427-A-C is described in ClinVar as [Benign]. Clinvar id is 1285997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSTA	NM_005213.4	c.169-12A>C		intron_variant		ENST00000264474.4	NP_005204.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSTA	ENST00000264474.4	c.169-12A>C		intron_variant		1	NM_005213.4	ENSP00000264474.3

Frequencies

GnomAD3 genomes AF: 0.0837 AC: 12718 AN: 152018 Hom.: 831 Cov.: 31

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0425

Gnomad ASJ AF: 0.0288

Gnomad EAS AF: 0.0144

Gnomad SAS AF: 0.0468

Gnomad FIN AF: 0.0853

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0474

Gnomad OTH AF: 0.0655

GnomAD3 exomes AF: 0.0553 AC: 13852 AN: 250682 Hom.: 589 AF XY: 0.0539 AC XY: 7309 AN XY: 135698

Gnomad AFR exome AF: 0.185

Gnomad AMR exome AF: 0.0232

Gnomad ASJ exome AF: 0.0272

Gnomad EAS exome AF: 0.0160

Gnomad SAS exome AF: 0.0511

Gnomad FIN exome AF: 0.0846

Gnomad NFE exome AF: 0.0516

Gnomad OTH exome AF: 0.0485

GnomAD4 exome AF: 0.0488 AC: 71336 AN: 1460894 Hom.: 2265 Cov.: 31 AF XY: 0.0487 AC XY: 35423 AN XY: 726824

Gnomad4 AFR exome AF: 0.179

Gnomad4 AMR exome AF: 0.0255

Gnomad4 ASJ exome AF: 0.0278

Gnomad4 EAS exome AF: 0.0129

Gnomad4 SAS exome AF: 0.0495

Gnomad4 FIN exome AF: 0.0838

Gnomad4 NFE exome AF: 0.0459

Gnomad4 OTH exome AF: 0.0499

GnomAD4 genome AF: 0.0837 AC: 12733 AN: 152136 Hom.: 831 Cov.: 31 AF XY: 0.0828 AC XY: 6155 AN XY: 74374

Gnomad4 AFR AF: 0.177

Gnomad4 AMR AF: 0.0424

Gnomad4 ASJ AF: 0.0288

Gnomad4 EAS AF: 0.0145

Gnomad4 SAS AF: 0.0464

Gnomad4 FIN AF: 0.0853

Gnomad4 NFE AF: 0.0474

Gnomad4 OTH AF: 0.0653

Alfa AF: 0.0635 Hom.: 110

Bravo AF: 0.0847

Asia WGS AF: 0.0440 AC: 154 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.39
DANN	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000040
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs6762112; hg19: chr3-122060274;