chr13-94590872-AAA-CAG

Variant names:

• chr13-94590872-AAA-CAG
• NM_014305.4:c.292_294delTTTinsCTG
• TGDS p.Phe98Leu

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+6 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 6 classification points (ACMG Germline Pathogenicity v2019). PS1_ModeratePM1PM2

The NM_014305.4(TGDS):c.292_294delTTTinsCTG (p.Phe98Leu) variant causes a missense change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TGDS NM_014305.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.75
• 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

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_pathogenic. The variant received 6 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS1Same amino acid change as known pathogenic		Same AA change, 0-star ClinVar pathogenic — moderate (PS1); ClinVar contains 1 P/LP entry with the same amino acid change (highest review level: 0 stars).
	PM1Mutational hot spot or critical domain		Single-residue UniProt domain with pathogenic enrichment (OR ≥ 3 vs. background) — PM1; Single-residue functional domain.; In-domain: 1 pathogenic, 0 benign rare missense variants (OR vs. background: 15.0).; ±8 AA neighbourhood: 3 pathogenic, 0 benign (OR vs. background: 35.0).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AR/unknown gene) — PM2; Absent from gnomAD at well-covered site (MOI: AR) (threshold 0.001) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_014305.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TGDS NM_014305.4	MANE Select	c.292_294delTTTinsCTG p.Phe98Leu	missense	N/A	Prot: NP_055120.1 UniProt:
	TGDS NM_001304430.2		c.196_198delTTTinsCTG p.Phe66Leu	missense	N/A	Prot: NP_001291359.1
	TGDS NR_130731.2		n.308_310delTTTinsCTG	non_coding_transcript_exon	Exon 4 of 12	Prot:

TGDS NM_014305.4

MANE Select

HGVSc / HGVSpc.292_294delTTTinsCTGp.Phe98Leu

Exon rankN/A

missense

Prot: NP_055120.1UniProt: O95455

TGDS NM_001304430.2

HGVSc / HGVSpc.196_198delTTTinsCTGp.Phe66Leu

Exon rankN/A

missense

Prot: NP_001291359.1

TGDS NR_130731.2

HGVSc / HGVSpn.308_310delTTTinsCTG

Exon rankExon 4 of 12

non_coding_transcript_exon

Prot:

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TGDS ENST00000261296.7	TSL:1MANE Select	c.292_294delTTTinsCTG p.Phe98Leu	missense	N/A	Prot: ENSP00000261296.5 UniProt:
	TGDS ENST00000953437.1		c.292_294delTTTinsCTG p.Phe98Leu	missense	N/A	Prot: ENSP00000623496.1 UniProt:
	TGDS ENST00000921421.1		c.223_225delTTTinsCTG p.Phe75Leu	missense	N/A	Prot: ENSP00000591480.1 UniProt:

TGDS ENST00000261296.7

TSL:1MANE Select

HGVSc / HGVSpc.292_294delTTTinsCTGp.Phe98Leu

Exon rankN/A

missense

Prot: ENSP00000261296.5UniProt: O95455

TGDS ENST00000953437.1

HGVSc / HGVSpc.292_294delTTTinsCTGp.Phe98Leu

Exon rankN/A

missense

Prot: ENSP00000623496.1UniProt: A0ACI8UR48

TGDS ENST00000921421.1

HGVSc / HGVSpc.223_225delTTTinsCTGp.Phe75Leu

Exon rankN/A

missense

Prot: ENSP00000591480.1UniProt: A0ACI8T2I5

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Uncertain	6.7

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr13-95243126;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar