chr6-116279302-T-TCAC

Variant names:

• chr6-116279302-T-TCAC
• rs56100880
• NM_003309.4:c.526_528dupGTG

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PM4_Supporting BP6_Very_Strong BA1

The NM_003309.4(TSPYL1):​c.526_528dupGTG​(p.Val176dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.684 in 1,609,234 control chromosomes in the GnomAD database, including 386,893 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.76 (45285 hom., cov: 0)
  • Exomes 𝑓: 0.68 (341608 hom.)
• Consequence: TSPYL1 NM_003309.4 conservative_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.225
• Publications: 5 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: Benign. The variant received -15 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_003309.4. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 6-116279302-T-TCAC is Benign according to our data. Variant chr6-116279302-T-TCAC is described in ClinVar as Benign. ClinVar VariationId is 1301648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.973 is higher than 0.05.

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.526_528dupGTG	p.Val176dup	conservative_inframe_insertion	Exon 1 of 1	NP_003300.1	Q9H0U9
	DSE	NM_001322937.2		c.-54+20340_-54+20342dupACC		intron	N/A	NP_001309866.1	Q9UL01
	DSE	NM_001322938.2		c.-54+20340_-54+20342dupACC		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.526_528dupGTG	p.Val176dup	conservative_inframe_insertion	Exon 1 of 1	ENSP00000357597.4	Q9H0U9
	DSE	ENST00000891542.1		c.-54+20340_-54+20342dupACC		intron	N/A	ENSP00000561601.1
	DSE	ENST00000891543.1		c.-263+20340_-263+20342dupACC		intron	N/A	ENSP00000561602.1

Frequencies

GnomAD3 genomes AF: 0.761 AC: 115322 AN: 151600 Hom.: 45227 Cov.: 0

Gnomad AFR AF: 0.922

Gnomad AMI AF: 0.649

Gnomad AMR AF: 0.762

Gnomad ASJ AF: 0.696

Gnomad EAS AF: 0.996

Gnomad SAS AF: 0.931

Gnomad FIN AF: 0.761

Gnomad MID AF: 0.657

Gnomad NFE AF: 0.639

Gnomad OTH AF: 0.720

GnomAD4 exome AF: 0.676 AC: 985557 AN: 1457516 Hom.: 341608 Cov.: 79 AF XY: 0.682 AC XY: 494778 AN XY: 725246

African (AFR) AF: 0.931 AC: 31176 AN: 33476

American (AMR) AF: 0.826 AC: 36923 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.682 AC: 17832 AN: 26136

East Asian (EAS) AF: 0.999 AC: 39649 AN: 39700

South Asian (SAS) AF: 0.914 AC: 78799 AN: 86258

European-Finnish (FIN) AF: 0.757 AC: 37225 AN: 49142

Middle Eastern (MID) AF: 0.735 AC: 4241 AN: 5768

European-Non Finnish (NFE) AF: 0.627 AC: 697611 AN: 1111944

Other (OTH) AF: 0.697 AC: 42101 AN: 60372

GnomAD4 genome AF: 0.761 AC: 115440 AN: 151718 Hom.: 45285 Cov.: 0 AF XY: 0.771 AC XY: 57141 AN XY: 74122

African (AFR) AF: 0.922 AC: 38176 AN: 41396

American (AMR) AF: 0.763 AC: 11639 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.696 AC: 2418 AN: 3472

East Asian (EAS) AF: 0.996 AC: 5115 AN: 5134

South Asian (SAS) AF: 0.930 AC: 4462 AN: 4796

European-Finnish (FIN) AF: 0.761 AC: 7981 AN: 10492

Middle Eastern (MID) AF: 0.672 AC: 195 AN: 290

European-Non Finnish (NFE) AF: 0.639 AC: 43343 AN: 67864

Other (OTH) AF: 0.724 AC: 1524 AN: 2106

Alfa AF: 0.695 Hom.: 6185

Asia WGS AF: 0.948 AC: 3296 AN: 3478

EpiCase AF: 0.629

EpiControl AF: 0.631

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Ehlers-Danlos syndrome, musculocontractural type 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.23
Mutation Taster		=81/19	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs56100880; hg19: chr6-116600465; COSMIC: COSV63993980; COSMIC: COSV63993980;