rs536094482

Variant names:

• chr20-45898716-T-A
• rs536094482
• NM_006227.4:c.*225A>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_006227.4(PLTP):​c.*225A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00054 in 662,808 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (1 hom.)
• Consequence: PLTP NM_006227.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.426
• Publications: 1 publications found

Genes affected

PLTP (HGNC:9093): (phospholipid transfer protein) The protein encoded by this gene is one of at least two lipid transfer proteins found in human plasma. The encoded protein transfers phospholipids from triglyceride-rich lipoproteins to high density lipoprotein (HDL). In addition to regulating the size of HDL particles, this protein may be involved in cholesterol metabolism. At least two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

CTSA (HGNC:9251): (cathepsin A) This gene encodes a member of the peptidase S10 family of serine carboxypeptidases. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate two chains that comprise the heterodimeric active enzyme. This enzyme possesses deamidase, esterase and carboxypeptidase activities and acts as a scaffold in the lysosomal multienzyme complex. Mutations in this gene are associated with galactosialidosis. [provided by RefSeq, Nov 2015]

CTSA Gene-Disease associations (from GenCC):

• galactosialidosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), Illumina, G2P, Genomics England PanelApp

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006227.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLTP	NM_006227.4	MANE Select	c.*225A>T		3_prime_UTR	Exon 16 of 16	NP_006218.1	P55058-1
	CTSA	NM_000308.4	MANE Select	c.*266T>A		3_prime_UTR	Exon 15 of 15	NP_000299.3	P10619-1
	CTSA	NM_001127695.3		c.*266T>A		3_prime_UTR	Exon 15 of 15	NP_001121167.1	P10619-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLTP	ENST00000372431.8	TSL:1 MANE Select	c.*225A>T		3_prime_UTR	Exon 16 of 16	ENSP00000361508.3	P55058-1
	CTSA	ENST00000646241.3	MANE Select	c.*266T>A		3_prime_UTR	Exon 15 of 15	ENSP00000493613.2	P10619-1
	CTSA	ENST00000372484.8	TSL:1	c.*266T>A		3_prime_UTR	Exon 15 of 15	ENSP00000361562.3	X6R8A1

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000957

GnomAD4 exome AF: 0.000593 AC: 303 AN: 510532 Hom.: 1 Cov.: 6 AF XY: 0.000707 AC XY: 190 AN XY: 268604

African (AFR) AF: 0.000143 AC: 2 AN: 13952

American (AMR) AF: 0.000792 AC: 18 AN: 22732

Ashkenazi Jewish (ASJ) AF: 0.00285 AC: 42 AN: 14732

East Asian (EAS) AF: 0.00 AC: 0 AN: 31606

South Asian (SAS) AF: 0.00242 AC: 118 AN: 48830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30340

Middle Eastern (MID) AF: 0.00233 AC: 5 AN: 2150

European-Non Finnish (NFE) AF: 0.000314 AC: 100 AN: 317976

Other (OTH) AF: 0.000638 AC: 18 AN: 28214

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.000416 AC XY: 31 AN XY: 74468

African (AFR) AF: 0.0000481 AC: 2 AN: 41552

American (AMR) AF: 0.00105 AC: 16 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68024

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000318 Hom.: 0

Bravo AF: 0.000382

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Combined deficiency of sialidase AND beta galactosidase (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	7.0
DANN	Benign	0.86
PhyloP100		-0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs536094482; hg19: chr20-44527355;