Variant 10-70139987-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000287078.7(TYSND1):c.1638G>C(p.Glu546Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000075 in 1,614,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

TYSND1
ENST00000287078.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.146

Variant links:

Genes affected

TYSND1 (HGNC:28531): (trypsin like peroxisomal matrix peptidase 1) This gene encodes a protease that removes the N-terminal peroxisomal targeting signal (PTS2) from proteins produced in the cytosol, thereby facilitating their import into the peroxisome. The encoded protein is also capable of removing the C-terminal peroxisomal targeting signal (PTS1) from proteins in the peroxisomal matrix. The full-length protein undergoes self-cleavage to produce shorter, potentially inactive, peptides. Alternative splicing results in multiple transcript variants for this gene. [provided by RefSeq, Jan 2013]

TYSND1 links:

TYSND1 (HGNC:):

TYSND1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.025560528).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TYSND1	NM_173555.4 linkuse as main transcript	c.1638G>C	p.Glu546Asp	missense_variant	4/4	ENST00000287078.7	NP_775826.2	Q2T9J0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TYSND1	ENST00000287078.7 linkuse as main transcript	c.1638G>C	p.Glu546Asp	missense_variant	4/4	1	NM_173555.4	ENSP00000287078.6	Q2T9J0-1
TYSND1	ENST00000335494 linkuse as main transcript	c.*124G>C		3_prime_UTR_variant	2/2	1		ENSP00000335673.5	Q2T9J0-2
TYSND1	ENST00000479086.1 linkuse as main transcript	n.616G>C		non_coding_transcript_exon_variant	4/4	2
TYSND1	ENST00000494143.5 linkuse as main transcript	n.1335G>C		non_coding_transcript_exon_variant	3/3	2

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

152262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000875

AC:

AN:

251340

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000410

AC:

AN:

1461806

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.000400

AC:

AN:

152380

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74518

show subpopulations

Gnomad4 AFR

AF:

0.00130

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.000434

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000988

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2023

The c.1638G>C (p.E546D) alteration is located in exon 4 (coding exon 4) of the TYSND1 gene. This alteration results from a G to C substitution at nucleotide position 1638, causing the glutamic acid (E) at amino acid position 546 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.011

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.60

M_CAP

Benign

0.0090

MetaRNN

Benign

0.026

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

MutationTaster

Benign

1.0

D;N

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.5

REVEL

Benign

0.038

Sift

Benign

0.11

Sift4G

Benign

0.30

Polyphen

0.84

Vest4

0.090

MutPred

0.38

Gain of sheet (P = 0.0827);

MVP

0.56

ClinPred

0.0079

GERP RS

3.1

Varity_R

0.12

gMVP

0.41

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over