6-116278911-A-G

Position:

• chr6-116278911-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003309.4(TSPYL1):​c.920T>C​(p.Leu307Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSPYL1 NM_003309.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.00

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.955

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSPYL1	NM_003309.4	c.920T>C	p.Leu307Ser	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.920T>C	p.Leu307Ser	missense_variant	1/1		NM_003309.4	ENSP00000357597	P1
DSE	ENST00000430252.6	c.-54+19944A>G		intron_variant		2		ENSP00000397597
DSE	ENST00000647244.1	c.-54+19944A>G		intron_variant				ENSP00000495184
TSPYL1	ENST00000652202.1	c.920T>C	p.Leu307Ser	missense_variant, NMD_transcript_variant	1/3			ENSP00000498597

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Sudden infant death-dysgenesis of the testes syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense variant p.L307S in TSPYL1 (NM_003309.4) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.L307S variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. There is a large physicochemical difference between leucine and serine, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. The p.L307S missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.920 in TSPYL1 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.098	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.60	T
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.85		Gain of disorder (P = 0.0121);
MVP		0.71
MPC		1.7
ClinPred		1.0	D
GERP RS		4.2
Varity_R		0.91
gMVP		0.90

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: rs1773301663; hg19: chr6-116600074;