3-122341557-C-T

Position:

• chr3-122341557-C-T

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.287C>T​(p.Thr96Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,613,738 control chromosomes in the GnomAD database, including 15,124 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.11 (1161 hom., cov: 31)
  • Exomes 𝑓: 0.13 (13963 hom.)
• Consequence: CSTA NM_005213.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.79

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 (MetaRNN=0.0023583472).
• BP6: Variant 3-122341557-C-T is Benign according to our data. Variant chr3-122341557-C-T is described in ClinVar as [Benign]. Clinvar id is 1232816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSTA	NM_005213.4	c.287C>T	p.Thr96Met	missense_variant	3/3	ENST00000264474.4	NP_005204.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSTA	ENST00000264474.4	c.287C>T	p.Thr96Met	missense_variant	3/3	1	NM_005213.4	ENSP00000264474.3

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16863 AN: 152072 Hom.: 1161 Cov.: 31

Gnomad AFR AF: 0.0409

Gnomad AMI AF: 0.0450

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.267

Gnomad EAS AF: 0.0306

Gnomad SAS AF: 0.164

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.144

GnomAD3 exomes AF: 0.127 AC: 31915 AN: 251422 Hom.: 2367 AF XY: 0.134 AC XY: 18227 AN XY: 135884

Gnomad AFR exome AF: 0.0405

Gnomad AMR exome AF: 0.0931

Gnomad ASJ exome AF: 0.257

Gnomad EAS exome AF: 0.0273

Gnomad SAS exome AF: 0.178

Gnomad FIN exome AF: 0.128

Gnomad NFE exome AF: 0.138

Gnomad OTH exome AF: 0.160

GnomAD4 exome AF: 0.132 AC: 193422 AN: 1461548 Hom.: 13963 Cov.: 32 AF XY: 0.136 AC XY: 98629 AN XY: 727094

Gnomad4 AFR exome AF: 0.0395

Gnomad4 AMR exome AF: 0.0982

Gnomad4 ASJ exome AF: 0.259

Gnomad4 EAS exome AF: 0.0200

Gnomad4 SAS exome AF: 0.177

Gnomad4 FIN exome AF: 0.129

Gnomad4 NFE exome AF: 0.133

Gnomad4 OTH exome AF: 0.141

GnomAD4 genome AF: 0.111 AC: 16859 AN: 152190 Hom.: 1161 Cov.: 31 AF XY: 0.112 AC XY: 8304 AN XY: 74382

Gnomad4 AFR AF: 0.0409

Gnomad4 AMR AF: 0.135

Gnomad4 ASJ AF: 0.267

Gnomad4 EAS AF: 0.0303

Gnomad4 SAS AF: 0.164

Gnomad4 FIN AF: 0.131

Gnomad4 NFE AF: 0.139

Gnomad4 OTH AF: 0.141

Alfa AF: 0.138 Hom.: 2426

Bravo AF: 0.107

TwinsUK AF: 0.133 AC: 494

ALSPAC AF: 0.127 AC: 488

ESP6500AA AF: 0.0481 AC: 212

ESP6500EA AF: 0.148 AC: 1277

ExAC AF: 0.125 AC: 15156

Asia WGS AF: 0.102 AC: 354 AN: 3478

EpiCase AF: 0.146

EpiControl AF: 0.156

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	clinical testing	GeneDx	Nov 10, 2018	This variant is associated with the following publications: (PMID: 17441792) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	9.2
DANN	Benign	0.97
DEOGEN2	Uncertain	0.48	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.99	T
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.26
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.037	D
Polyphen		0.86	P
Vest4		0.071
MPC		0.30
ClinPred		0.043	T
GERP RS		-7.3
Varity_R		0.14
gMVP		0.40

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

Other links and lift over

dbSNP: rs34173813; hg19: chr3-122060404; COSMIC: COSV52612962; COSMIC: COSV52612962;