6-116279184-T-C

Variant names:

• chr6-116279184-T-C
• rs753490319
• NM_003309.4:c.647A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003309.4(TSPYL1):​c.647A>G​(p.Glu216Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E216V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSPYL1 NM_003309.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.285
• Publications: 0 publications found

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]

DSE Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome, musculocontractural type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, ClinGen, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• Ehlers-Danlos syndrome, musculocontractural type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054356486).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003309.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSPYL1	NM_003309.4	MANE Select	c.647A>G	p.Glu216Gly	missense	Exon 1 of 1	NP_003300.1	Q9H0U9
	DSE	NM_001322937.2		c.-54+20217T>C		intron	N/A	NP_001309866.1	Q9UL01
	DSE	NM_001322938.2		c.-54+20217T>C		intron	N/A	NP_001309867.1	Q9UL01

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSPYL1	ENST00000368608.4	TSL:6 MANE Select	c.647A>G	p.Glu216Gly	missense	Exon 1 of 1	ENSP00000357597.4	Q9H0U9
	DSE	ENST00000891542.1		c.-54+20217T>C		intron	N/A	ENSP00000561601.1
	DSE	ENST00000891543.1		c.-263+20217T>C		intron	N/A	ENSP00000561602.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0071	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.22	T
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.28
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.015
Sift	Benign	0.12	T
Sift4G	Benign	0.37	T
Polyphen		0.0030	B
Vest4		0.12
MutPred		0.25		Loss of helix (P = 0.0033)
MVP		0.25
MPC		0.63
ClinPred		0.059	T
GERP RS		-4.3
Varity_R		0.053
gMVP		0.32
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs753490319; hg19: chr6-116600347;