6-116278696-T-C

Position:

• chr6-116278696-T-C

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.1135A>G​(p.Thr379Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,614,102 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (4 hom., cov: 32)
  • Exomes 𝑓: 0.011 (97 hom.)
• Consequence: TSPYL1 NM_003309.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.03

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=0.009389162).
• BP6: Variant 6-116278696-T-C is Benign according to our data. Variant chr6-116278696-T-C is described in ClinVar as [Benign]. Clinvar id is 773200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSPYL1	NM_003309.4	c.1135A>G	p.Thr379Ala	missense_variant	1/1	ENST00000368608.4	NP_003300.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSPYL1	ENST00000368608.4	c.1135A>G	p.Thr379Ala	missense_variant	1/1		NM_003309.4	ENSP00000357597	P1
DSE	ENST00000430252.6	c.-54+19729T>C		intron_variant		2		ENSP00000397597
DSE	ENST00000647244.1	c.-54+19729T>C		intron_variant				ENSP00000495184
TSPYL1	ENST00000652202.1	c.1135A>G	p.Thr379Ala	missense_variant, NMD_transcript_variant	1/3			ENSP00000498597

Frequencies

GnomAD3 genomes AF: 0.00686 AC: 1044 AN: 152096 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00215

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0126

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.00384

GnomAD3 exomes AF: 0.00715 AC: 1797 AN: 251450 Hom.: 10 AF XY: 0.00704 AC XY: 957 AN XY: 135904

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.0132

Gnomad NFE exome AF: 0.0121

Gnomad OTH exome AF: 0.00668

GnomAD4 exome AF: 0.0106 AC: 15488 AN: 1461888 Hom.: 97 Cov.: 32 AF XY: 0.0102 AC XY: 7409 AN XY: 727246

Gnomad4 AFR exome AF: 0.00212

Gnomad4 AMR exome AF: 0.00130

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.0140

Gnomad4 NFE exome AF: 0.0127

Gnomad4 OTH exome AF: 0.00659

GnomAD4 genome AF: 0.00686 AC: 1044 AN: 152214 Hom.: 4 Cov.: 32 AF XY: 0.00626 AC XY: 466 AN XY: 74426

Gnomad4 AFR AF: 0.00214

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0126

Gnomad4 NFE AF: 0.0114

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.0104 Hom.: 22

Bravo AF: 0.00612

TwinsUK AF: 0.0132 AC: 49

ALSPAC AF: 0.0122 AC: 47

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.0126 AC: 108

ExAC AF: 0.00761 AC: 924

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	TSPYL1: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 27, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.0023	T
Eigen	Benign	-0.095
Eigen_PC	Benign	0.035
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.21	T
MetaRNN	Benign	0.0094	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.80	N
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.046
Sift	Benign	0.27	T
Sift4G	Benign	0.10	T
Polyphen		0.050	B
Vest4		0.30
MVP		0.35
MPC		0.72
ClinPred		0.0071	T
GERP RS		4.3
Varity_R		0.21
gMVP		0.25

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: rs45490498; hg19: chr6-116599859;