3-122341543-G-T

Position:

• chr3-122341543-G-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.273G>T​(p.Lys91Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00348 in 1,614,096 control chromosomes in the GnomAD database, including 184 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (105 hom., cov: 31)
  • Exomes 𝑓: 0.0019 (79 hom.)
• Consequence: CSTA NM_005213.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0440

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=0.0029422045).
• BP6: Variant 3-122341543-G-T is Benign according to our data. Variant chr3-122341543-G-T is described in ClinVar as [Benign]. Clinvar id is 767925.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0617 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSTA	NM_005213.4	c.273G>T	p.Lys91Asn	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.273G>T	p.Lys91Asn	missense_variant	3/3	1	NM_005213.4	ENSP00000264474.3

Frequencies

GnomAD3 genomes AF: 0.0184 AC: 2803 AN: 152138 Hom.: 104 Cov.: 31

Gnomad AFR AF: 0.0636

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00766

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00478 AC: 1202 AN: 251442 Hom.: 42 AF XY: 0.00352 AC XY: 479 AN XY: 135892

Gnomad AFR exome AF: 0.0621

Gnomad AMR exome AF: 0.00411

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00192 AC: 2809 AN: 1461840 Hom.: 79 Cov.: 31 AF XY: 0.00159 AC XY: 1154 AN XY: 727230

Gnomad4 AFR exome AF: 0.0651

Gnomad4 AMR exome AF: 0.00441

Gnomad4 ASJ exome AF: 0.000918

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000746

Gnomad4 OTH exome AF: 0.00482

GnomAD4 genome AF: 0.0185 AC: 2814 AN: 152256 Hom.: 105 Cov.: 31 AF XY: 0.0186 AC XY: 1387 AN XY: 74462

Gnomad4 AFR AF: 0.0637

Gnomad4 AMR AF: 0.00765

Gnomad4 ASJ AF: 0.000866

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00974 Hom.: 28

Bravo AF: 0.0212

ESP6500AA AF: 0.0579 AC: 255

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00581 AC: 706

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.81	T
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.33
Sift	Benign	0.037	D
Sift4G	Benign	0.10	T
Polyphen		0.95	P
Vest4		0.17
MutPred		0.46		Loss of ubiquitination at K91 (P = 0.0034);
MVP		0.87
MPC		0.55
ClinPred		0.044	T
GERP RS		3.6
Varity_R		0.80
gMVP		0.51

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: rs34021626; hg19: chr3-122060390;