13-94590894-TTC-T

Variant names:

• chr13-94590894-TTC-T
• rs727502809
• NM_014305.4:c.270_271delGA

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP5

The NM_014305.4(TGDS):​c.270_271delGA​(p.Lys91AsnfsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,577,108 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: TGDS NM_014305.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 3.21
• Publications: 0 publications found

Genes affected

TGDS (HGNC:20324): (TDP-glucose 4,6-dehydratase) The protein encoded by this gene is a member of the short-chain dehydrogenases/reductases (SDR) superfamily, and is thought to contain a nicotinamide adenine dinucleotide (NAD) binding domain. This large SDR family of enzymes is involved in the metabolism of a variety of compounds, including prostaglandins, retinoids, lipids, steroid hormones, and xenobiotics. Mutations in this gene have been associated with Catel-Manzke syndrome, which is characterized by Pierre Robin sequence, and radial deviation of the index finger due to the presence of an accessory bone between the index finger and its proximal phalanx. Pierre Robin sequence is defined by an undersized jaw, backwards displacement of the tongue base that causes an obstruction of the airways, and can also be associated with a cleft palate. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2015]

TGDS Gene-Disease associations (from GenCC):

• Catel-Manzke syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Orphanet, ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP5: Variant 13-94590894-TTC-T is Pathogenic according to our data. Variant chr13-94590894-TTC-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 162459.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014305.4. 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
	TGDS	NM_014305.4	MANE Select	c.270_271delGA	p.Lys91AsnfsTer22	frameshift	Exon 4 of 12	NP_055120.1	O95455
	TGDS	NM_001304430.2		c.174_175delGA	p.Lys59AsnfsTer22	frameshift	Exon 4 of 12	NP_001291359.1
	TGDS	NR_130731.2		n.286_287delGA		non_coding_transcript_exon	Exon 4 of 12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGDS	ENST00000261296.7	TSL:1 MANE Select	c.270_271delGA	p.Lys91AsnfsTer22	frameshift	Exon 4 of 12	ENSP00000261296.5	O95455
	TGDS	ENST00000953437.1		c.270_271delGA	p.Lys91AsnfsTer22	frameshift	Exon 4 of 12	ENSP00000623496.1
	TGDS	ENST00000921421.1		c.201_202delGA	p.Lys68AsnfsTer22	frameshift	Exon 3 of 11	ENSP00000591480.1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000185 AC: 4 AN: 216584 AF XY: 0.0000169

Gnomad AFR exome AF: 0.000209

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000963

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000211 AC: 30 AN: 1424918 Hom.: 0 AF XY: 0.0000212 AC XY: 15 AN XY: 708216

African (AFR) AF: 0.000162 AC: 5 AN: 30818

American (AMR) AF: 0.00 AC: 0 AN: 34154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25024

East Asian (EAS) AF: 0.00 AC: 0 AN: 37750

South Asian (SAS) AF: 0.00 AC: 0 AN: 78556

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.0000218 AC: 24 AN: 1100822

Other (OTH) AF: 0.0000170 AC: 1 AN: 58952

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152190 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74338

African (AFR) AF: 0.000217 AC: 9 AN: 41442

American (AMR) AF: 0.000196 AC: 3 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000102

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	not provided (2)
1	-	-	Catel-Manzke syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.2
Mutation Taster		=11/189	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs727502809; hg19: chr13-95243148;