20-23637934-T-A

Variant names:

• chr20-23637934-T-A
• rs73318135
• NM_000099.4:c.-72A>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000099.4(CST3):​c.-72A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000268 in 1,270,608 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000029 (0 hom.)
• Consequence: CST3 NM_000099.4 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.00001703
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.54
• Publications: 14 publications found

Genes affected

CST3 (HGNC:2475): (cystatin C) 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 the kininogens. The type 2 cystatin proteins are a class of cysteine proteinase inhibitors found in a variety of human fluids and secretions, where they appear to provide protective functions. The cystatin locus on chromosome 20 contains the majority of the type 2 cystatin genes and pseudogenes. This gene is located in the cystatin locus and encodes the most abundant extracellular inhibitor of cysteine proteases, which is found in high concentrations in biological fluids and is expressed in virtually all organs of the body. A mutation in this gene has been associated with amyloid angiopathy. Expression of this protein in vascular wall smooth muscle cells is severely reduced in both atherosclerotic and aneurysmal aortic lesions, establishing its role in vascular disease. In addition, this protein has been shown to have an antimicrobial function, inhibiting the replication of herpes simplex virus. Alternative splicing results in multiple transcript variants encoding a single protein. [provided by RefSeq, Nov 2014]

CST3 Gene-Disease associations (from GenCC):

• ACys amyloidosis

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000286117 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BS2: High AC in GnomAdExome4 at 32 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000099.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CST3	NM_000099.4	MANE Select	c.-72A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	NP_000090.1
	CST3	NM_000099.4	MANE Select	c.-72A>T		5_prime_UTR	Exon 1 of 3	NP_000090.1
	CST3	NM_001288614.2		c.-72A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	NP_001275543.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CST3	ENST00000376925.8	TSL:1 MANE Select	c.-72A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 3	ENSP00000366124.3
	CST3	ENST00000398411.5	TSL:1	c.-72A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	ENSP00000381448.1
	CST3	ENST00000376925.8	TSL:1 MANE Select	c.-72A>T		5_prime_UTR	Exon 1 of 3	ENSP00000366124.3

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 150272 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000213

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000286 AC: 32 AN: 1120336 Hom.: 0 Cov.: 31 AF XY: 0.0000333 AC XY: 18 AN XY: 540036

African (AFR) AF: 0.00 AC: 0 AN: 21262

American (AMR) AF: 0.00 AC: 0 AN: 6922

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13164

East Asian (EAS) AF: 0.00 AC: 0 AN: 19576

South Asian (SAS) AF: 0.0000225 AC: 1 AN: 44470

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22158

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2878

European-Non Finnish (NFE) AF: 0.0000317 AC: 30 AN: 946308

Other (OTH) AF: 0.0000229 AC: 1 AN: 43598

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 150272 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 73342

African (AFR) AF: 0.00 AC: 0 AN: 41164

American (AMR) AF: 0.00 AC: 0 AN: 15166

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 4346

South Asian (SAS) AF: 0.000213 AC: 1 AN: 4696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67744

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.00 Hom.: 886

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	2.3
DANN	Benign	0.46
PhyloP100		-3.5
PromoterAI		0.014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000017
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

Other links and lift over

dbSNP: rs73318135; hg19: chr20-23618571;