6-116279290-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003309.4(TSPYL1):c.541G>A(p.Ala181Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,565,222 control chromosomes in the GnomAD database, including 18,744 homozygotes. 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 Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.23 (2298 hom., cov: 32)
  • Exomes 𝑓: 0.15 (16446 hom.)
• Consequence: TSPYL1 NM_003309.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.389

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00415805).
• BP6: Variant 6-116279290-C-T is Benign according to our data. Variant chr6-116279290-C-T is described in ClinVar as [Benign]. Clinvar id is 1601556.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.379 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSPYL1	NM_003309.4	c.541G>A	p.Ala181Thr	missense_variant	1/1	ENST00000368608.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSPYL1	ENST00000368608.4	c.541G>A	p.Ala181Thr	missense_variant	1/1		NM_003309.4	P1

Frequencies

GnomAD3 genomes AF: 0.232 AC: 24964 AN: 107764 Hom.: 2295 Cov.: 32

Gnomad AFR AF: 0.385

Gnomad AMI AF: 0.0968

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.223

Gnomad EAS AF: 0.168

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.245

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.194

GnomAD3 exomes AF: 0.141 AC: 34291 AN: 243358 Hom.: 2617 AF XY: 0.143 AC XY: 18873 AN XY: 132078

Gnomad AFR exome AF: 0.239

Gnomad AMR exome AF: 0.0635

Gnomad ASJ exome AF: 0.177

Gnomad EAS exome AF: 0.0550

Gnomad SAS exome AF: 0.153

Gnomad FIN exome AF: 0.208

Gnomad NFE exome AF: 0.149

Gnomad OTH exome AF: 0.132

GnomAD4 exome AF: 0.147 AC: 213599 AN: 1457382 Hom.: 16446 Cov.: 39 AF XY: 0.147 AC XY: 106705 AN XY: 725224

Gnomad4 AFR exome AF: 0.248

Gnomad4 AMR exome AF: 0.0692

Gnomad4 ASJ exome AF: 0.179

Gnomad4 EAS exome AF: 0.0520

Gnomad4 SAS exome AF: 0.156

Gnomad4 FIN exome AF: 0.178

Gnomad4 NFE exome AF: 0.147

Gnomad4 OTH exome AF: 0.147

GnomAD4 genome AF: 0.232 AC: 24989 AN: 107840 Hom.: 2298 Cov.: 32 AF XY: 0.236 AC XY: 12238 AN XY: 51828

Gnomad4 AFR AF: 0.385

Gnomad4 AMR AF: 0.152

Gnomad4 ASJ AF: 0.223

Gnomad4 EAS AF: 0.169

Gnomad4 SAS AF: 0.339

Gnomad4 FIN AF: 0.245

Gnomad4 NFE AF: 0.175

Gnomad4 OTH AF: 0.195

Alfa AF: 0.144 Hom.: 3583

Bravo AF: 0.160

TwinsUK AF: 0.151 AC: 559

ALSPAC AF: 0.152 AC: 585

ESP6500AA AF: 0.233 AC: 1026

ESP6500EA AF: 0.147 AC: 1260

ExAC AF: 0.143 AC: 17346

Asia WGS AF: 0.131 AC: 456 AN: 3466

EpiCase AF: 0.142

EpiControl AF: 0.138

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.84	T
BayesDel_noAF	Benign	-0.83
Cadd	Benign	1.7
Dann	Benign	0.75
DEOGEN2	Benign	0.00062	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.81	N
REVEL	Benign	0.082
Sift	Benign	0.59	T
Sift4G	Benign	0.21	T
Polyphen		0.0040	B
Vest4		0.017
MPC		0.52
ClinPred		0.0051	T
GERP RS		-5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.036
gMVP		0.042

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: rs3749894; hg19: chr6-116600453; COSMIC: COSV63994107; COSMIC: COSV63994107;