6-116278733-G-T

Position:

chr6-116278733-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_003309.4(TSPYL1):c.1098C>A(p.Phe366Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00403 in 1,614,174 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0026 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0042 ( 19 hom. )

Consequence

TSPYL1
NM_003309.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.05

Variant links:

Genes affected

TSPYL1 (HGNC:12382): (TSPY like 1) The protein encoded by this gene is found in the nucleolus and is similar to that of a family of genes on the Y-chromosome. This gene is intronless. Defects in this gene are a cause of sudden infant death with dysgenesis of the testes syndrome (SIDDT). [provided by RefSeq, Dec 2009]

TSPYL1 links:

DSE (HGNC:21144): (dermatan sulfate epimerase) The protein encoded by this gene is a tumor-rejection antigen. It is localized to the endoplasmic reticulum and functions to convert D-glucuronic acid to L-iduronic acid during the biosynthesis of dermatan sulfate. This antigen possesses tumor epitopes capable of inducing HLA-A24-restricted and tumor-specific cytotoxic T lymphocytes in cancer patients and may be useful for specific immunotherapy. Mutations in this gene cause inmusculocontractural Ehlers-Danlos syndrome. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 9, and a paralogous gene exists on chromosome 18. [provided by RefSeq, Apr 2016]

DSE links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005413294).

BP6

Variant 6-116278733-G-T is Benign according to our data. Variant chr6-116278733-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 718447.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSPYL1	NM_003309.4 linkuse as main transcript	c.1098C>A	p.Phe366Leu	missense_variant	1/1	ENST00000368608.4	NP_003300.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
TSPYL1	ENST00000368608.4 linkuse as main transcript	c.1098C>A	p.Phe366Leu	missense_variant	1/1		NM_003309.4	ENSP00000357597	P1
DSE	ENST00000430252.6 linkuse as main transcript	c.-54+19766G>T		intron_variant		2		ENSP00000397597
DSE	ENST00000647244.1 linkuse as main transcript	c.-54+19766G>T		intron_variant				ENSP00000495184
TSPYL1	ENST00000652202.1 linkuse as main transcript	c.1098C>A	p.Phe366Leu	missense_variant, NMD_transcript_variant	1/3			ENSP00000498597

Frequencies

GnomAD3 genomes

AF:

0.00261

AC:

398

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00692

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00600

Gnomad FIN

AF:

0.000753

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00398

Gnomad OTH

AF:

0.00526

GnomAD3 exomes

AF:

0.00358

AC:

899

AN:

251404

Hom.:

AF XY:

0.00382

AC XY:

519

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.00231

Gnomad ASJ exome

AF:

0.00764

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00882

Gnomad FIN exome

AF:

0.000462

Gnomad NFE exome

AF:

0.00380

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00418

AC:

6115

AN:

1461850

Hom.:

Cov.:

AF XY:

0.00423

AC XY:

3075

AN XY:

727220

show subpopulations

Gnomad4 AFR exome

AF:

0.000687

Gnomad4 AMR exome

AF:

0.00237

Gnomad4 ASJ exome

AF:

0.00853

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00795

Gnomad4 FIN exome

AF:

0.000487

Gnomad4 NFE exome

AF:

0.00432

Gnomad4 OTH exome

AF:

0.00406

GnomAD4 genome

AF:

0.00261

AC:

398

AN:

152324

Hom.:

Cov.:

AF XY:

0.00256

AC XY:

191

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000794

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.00692

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00601

Gnomad4 FIN

AF:

0.000753

Gnomad4 NFE

AF:

0.00398

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.00395

Hom.:

Bravo

AF:

0.00261

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00500

AC:

ExAC

AF:

0.00367

AC:

446

Asia WGS

AF:

0.00751

AC:

AN:

3478

EpiCase

AF:

0.00403

EpiControl

AF:

0.00421

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 20, 2023	- -

not specified

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 13, 2022

- -

TSPYL1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 22, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.0025

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.18

M_CAP

Benign

0.0050

MetaRNN

Benign

0.0054

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.020

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-1.1

REVEL

Benign

0.073

Sift

Benign

0.80

Sift4G

Benign

0.99

Polyphen

0.050

Vest4

0.16

MutPred

0.37

Gain of glycosylation at S365 (P = 0.0927);

MVP

0.32

MPC

0.67

ClinPred

0.011

GERP RS

2.5

Varity_R

0.18

gMVP

0.44

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