6-116278733-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.05

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]

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]

ACMG classification

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 GnomAdExome at 3 AR gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00261 AC: 398 AN: 152206 Hom.: 1 Cov.: 32

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.: 3 AF XY: 0.00382 AC XY: 519 AN XY: 135878

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.: 19 Cov.: 32 AF XY: 0.00423 AC XY: 3075 AN XY: 727220

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.: 1 Cov.: 32 AF XY: 0.00256 AC XY: 191 AN XY: 74486

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.: 2

Bravo AF: 0.00261

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00500 AC: 43

ExAC AF: 0.00367 AC: 446

Asia WGS AF: 0.00751 AC: 26 AN: 3478

EpiCase AF: 0.00403

EpiControl AF: 0.00421

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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, criteria provided, single submitter

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). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 20, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	20
Dann	Benign	0.90
DEOGEN2	Benign	0.0025	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.18	T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.020	N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.073
Sift	Benign	0.80	T
Sift4G	Benign	0.99	T
Polyphen		0.050	B
Vest4		0.16
MutPred		0.37		Gain of glycosylation at S365 (P = 0.0927);
MVP		0.32
MPC		0.67
ClinPred		0.011	T
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

Other links and lift over

dbSNP: rs140756663; hg19: chr6-116599896;